Clinical trial NCT04918147
Conditions: IgG4 Related Disease IgG4-RD
Keywords: immune-mediated fibroinflammatory disease prospective trial safety and efficacy IgG4-RD Responder Index (IgG4-RD RI)
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2021-10-13; Completion date: 2024-01-04
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a two-part multi-center clinical trial in participants with active IgG4-RD.

Part 1 (Cohort 1a and Cohort 1B) is an open-label, dose escalation phase to determine the safety of elotuzumab for investigation in IgG4-RD.

Part 2 (Cohort 2) is a randomized, placebo-controlled, double-blinded (masked) trial phase to compare the effects of elotuzumab and prednisone to elotuzumab placebo and prednisone in participants with IgG4 RD.

Approximately 75 participants with active IgG4-RD will be enrolled in the overall program, 12 in Part 1 and 63 in Part 2. Randomization in Part 2: 2 to 1, with approximately forty-two participants randomized to elotuzumab plus prednisone taper, and twenty-one participants randomized to placebo for elotuzumab plus prednisone taper.

The total duration of participation for each participant in this trial will be 48 weeks (11 months).

Detailed description:
Immunoglobulin G4-Related Disease (IgG4-RD) is a chronic fibro-inflammatory condition that can affect virtually every organ system, including the pancreas, biliary tract, salivary and lacrimal glands, orbits, lungs, kidneys, meninges, pituitary gland, prostate and thyroid. It may also involve the retroperitoneum. This multi-organ immune-mediated condition, once regarded as a group of isolated, single-organ diseases, is now recognized to be an overarching, single-disease entity linked by common histopathological and immunohistochemical features.

IgG4-RD tends to afflict middle-aged to elderly individuals. Although IgG4-RD can affect a single organ at presentation, it is not uncommon for participants to present with or develop multi-organ disease. As the disease progresses, additional organs develop lesions and the cellular inflammation characterizing early disease moves toward a more fibrotic stage, causing major tissue damage, dysfunction and ultimately organ failure. It is unclear whether IgG4 itself is involved in the pathogenesis of the disease.

The goals of IgG4-RD treatment are to reduce inflammation and organ swelling and to prevent or reverse tissue fibrosis. No approved therapy exists for IgG4-RD.

This study will enroll adult participants who meet the 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria for IgG4-RD, and who have active IgG4-RD with disease manifestations in at least two organ systems.

Primary study objectives:

* To determine the safety and tolerability of the addition of elotuzumab to prednisone in participants with IgG4-RD, and
* To compare the effect of the addition of elotuzumab versus placebo to prednisone on the IgG4-RD Responder Index (IgG4-RD RI), a measure of IgG4-RD disease activity.

Arms: arm 1: Per protocol: Six participants will receive elotuzumab on days 0,7, 14, 21, and the prescribed 10-week prednisone taper.

* Elotuzumab: 10 mg/kg administered once weekly, intravenously for 4 doses, per protocol.
* Prednisone taper (Pred Taper): Prescribed 10-week dosing taper beginning on Day 0 (baseline) that is taken orally (by mouth) daily, per protocol. Dosage in milligrams (mgs). arm 2: Per protocol: Six participants will receive elotuzumab over a 48 week period, dose of 10mg/kg IV x 1, at baseline, then at weeks 8, 16, 24, 32 and 40 (for a total of 6 doses), with the prescribed 10-week prednisone taper.

* Elotuzumab: 10 mg/kg administered as referenced above, intravenously, per protocol.
* Prednisone taper (Pred Taper): Prescribed 10-week dosing taper beginning on Day 0 (baseline) that is taken orally (by mouth) daily, per protocol. Dosage in milligrams (mgs). arm 3: Safety and efficacy analyses from Cohort 1a and Cohort 1b will occur prior to initiating Cohort 2 (Randomized).

Assuming no safety signal for Cohort 1, forty-two participants will receive elotuzumab per the regimen prescribed above in Part 1B, with the prescribed 10-week prednisone taper.

* Elotuzumab: 10 mg/kg administered as referenced above, intravenously, per protocol.
* Prednisone taper (Pred Taper): Prescribed 10-week dosing taper beginning on Day 0 that is taken daily by mouth, per protocol. Dosage in milligrams (mgs). arm 4: Safety and efficacy analyses from Cohort 1a and Cohort 1b will occur prior to initiating Cohort 2 (Randomized).

Twenty-one participants will receive placebo for elotuzumab on day 0, then weeks 8, 16, 24, 32 and 40, and the prescribed 10-week prednisone taper.

* Placebo for elotuzumab: Administered on same schedule as elotuzumab described in Cohort 2 Arm A: intravenously, per protocol.
* Prednisone taper (Pred Taper): Prescribed 10-week dosing taper beginning on Day 0 taken daily by mouth, per protocol. Dosage in milligrams (mgs).
Interventions: intervention 1: elotuzumab intervention 2: placebo for elotuzumab intervention 3: methylprednisolone intervention 4: diphenhydramine intervention 5: acetaminophen intervention 6: famotidine intervention 7: prednisone
Intervention descriptions: intervention 1: Elotuzumab is a humanized recombinant monoclonal antibody (mAb) targeted against SLAMF7, a cell surface glycoprotein. intervention 2: The placebo for elotuzumab is 0.9% sterile normal saline for injection. intervention 3: Premedication administered intravenously, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg). intervention 4: Premedication administered orally or intravenously, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg). intervention 5: Premedication administered orally, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg). intervention 6: Premedication administered orally or intravenously, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg). intervention 7: Prescribed dosing with prednisone begins on the day of the first elotuzumab/placebo infusion, administered orally. The ten-week dosing taper proceeds, per protocol. Dosage in milligrams (mg).

Protocol documents:
ICF_001.pdf: 
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Protocol Title:       
 
Principal Investigator:       
 
Site Principal Investigator:       
 
Description of Subject Population:       
 
 
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form.  
 
If you decide to take part in this research study, you must sign this form to show that you want to 
take part.  We will give you a signed copy of this form to keep.
 
 
Key Information 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  Your decision won’t change the 
medical care you get within [insert site name] now or in the future.   
 
The following key information is to help you decide whether or not to take part in this research 
study.  We have included more details about the research in the Detailed Information section that 
follows the key information.  
 
Why is this research study being done? 
 
You are being asked to take part in this research study because you have immunoglobulin G4-
related disease (IgG4-RD) that is currently active. The purpose of this study is to better 
understand the safety and side effects of an investigational drug called elotuzumab and to find 
what dose to use in people with IgG4-RD. 
 
How long will you take part in this research study? 
This is Part 1 of a planned 2-part study.  No one participates in both parts.  Part 1 is testing the 
safety of two different dosing schedules of elotuzumab.  This is a 1-year study for people with 
active IgG4-RD.  Part 1A of the study enrolled 6 participants as planned to test a weekly 
schedule of a study drug called elotuzumab given by IV infusion each week for 4 weeks (total of 


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4 doses). An oral corticosteroid (Prednisone) taper was started at the time of the first dose that 
was finished in 10 weeks. A safety review was conducted when the 6th person finished his/her 
infusions and Prednisone taper. No safety concerns were identified and now we are moving to 
Part 1B. In this part 6 additional participants will be enrolled and given a different schedule of IV 
elotuzumab, which will be administered as an infusion every 2 months for a total of 6 doses. The 
Prednisone taper will be given the same way as in Part 1A. The purpose of the more spread- out 
doses is to continue to evaluate safety of the study drug while looking at its durability (long term 
effect) on IgG4-RD. During this time, we will ask you to visit the study site about once a month 
(16 visits).   
 
What will happen if you take part in this research study? 
 
If you decide to join this research study, the following things will be done at various times in the 
study: physical exam, study drug infusions though an IV catheter, blood sample collection, 
urinalysis and urine pregnancy testing, possible CT (computed tomography) or MRI (magnetic 
resonance imaging) imaging, and have you fill out surveys about your health.  
 
Why might you choose to take part in this study? 
We cannot promise any benefits to you from taking part in this research study.  However, if you 
do receive elotuzumab, some of your IgG4-RD symptoms could possibly improve.  Others with 
IgG4-RD may benefit in the future from what we learn in this study.  
 
Why might you choose NOT to take part in this study? 
 
Taking part in this research study has some risks and requirements that you should consider 
carefully.  This is a research study of an investigational drug that will be tested for the first time 
in patients with your disease.  Side effects of elotuzumab reported in cancer patients include 
infusion reaction, infection, and liver problems.  This study will use a less intensive treatment 
period than what is used to treat cancer.  To try to reduce the risk of a reaction to elotuzumab, 
pre-medications will be given before each infusion, and you will be carefully monitored.  As 
with all medications, there can be side effects.  A detailed description of side effects can be 
found later in this consent form in the section called “What are the risks and possible discomforts 
from being in this research study?”  Other things to consider are travel commitments for clinic 
visits.  This study also involves at least 1 phone call visit where we will check in with you over 
the phone and/or computer after the first infusion to see how you are doing. If it is thought 
necessary for your health and well-being you may be asked to visit the study site for an 
unscheduled visit for a safety check. 
 
What other treatments or procedures are available for your condition? 
 


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You do not have to take part in this research study to be treated for IgG4-RD.    
  
There is no cure for IgG4-RD. However, there are medications, such as glucocorticosteroids 
(prednisone) available to manage some symptoms of IgG4-RD. Alternative options that may be 
available to you include treatment with other medicines for IgG4-RD such as rituximab.  
  
Talk with the study doctor if you have questions about any of these treatments or procedures.
 
If you have questions or concerns about this research study, whom can 
you call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.  
 
Dr. John Stone is the person in charge of this research study.  You can call him at 
M-F 9-5. You can also call Dr. Z
e or Dr. 
at 6
M F 9-5 
with questions about this research study. You can also call page Dr. Z
e or Dr. 
 at 6
2000 24/7. 
 
If you have questions about the scheduling of appointments or study visits, call the study 
coordinator at 6
 
 
If you want to speak with someone not directly involved in this research study, please contact 
the Mass General Brigham IRB.  You can call them at 8
0. 
 
You can talk to them about: 
 Your rights as a research subject 
 Your concerns about the research 
 A complaint about the research 
 Any pressure to take part in, or to continue in the research study
 
Detailed Information 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this website at any time. 
 
IgG4-RD is a chronic inflammatory and fibrotic condition that can affect virtually every organ 
system in the body. Some systems commonly affected are the pancreas, bile ducts, salivary and 
other glands and lymph nodes, peri-orbital area (around the eyes), lungs and kidneys. Over time, 
the inflammation becomes a more fibrotic “hardened, like scarring” condition that can lead to 
tissue damage and eventual organ failure if not treated. 
 


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Current treatment for IgG4-RD is primarily with corticosteroids (prednisone, methylprednisolone 
and others). While this approach is initially successful in most patients, the relapse rate is high 
when corticosteroid treatment is stopped. It is well-known that corticosteroids have side effects 
and long-term toxicities including glucose intolerance/diabetes, hypertension, weight gain, 
osteoporosis, increased risk of infection, glaucoma, cataracts and mood swings. More targeted 
treatments with other immunosuppressive drugs have been studied in small trials but no drug is 
approved by the U.S. Food and Drug Administration (FDA) for the treatment of IgG4-RD.   
 
Elotuzumab targets the immune system, and specifically the B and T cells thought to be active in 
IgG4-RD. The drug targets SLAMF7, a protein found on cells of the immune system thought to 
be a key factor to the development of IgG4-RD. Elotuzumab is currently approved by the U.S. 
FDA for the treatment of a type of blood cancer called multiple myeloma. Elotuzumab has not 
been studied in IgG4-RD or any other autoimmune disease until now. For Ig4-RD the drug is 
experimental and can only be used in research studies. 
 
This is Part 1 of a planned 2-part study.  Part 1 is testing the safety of two different dosing 
schedules of Elotuzumab.  This is a 1-year study for people with active IgG4-RD.  Part 1A of the 
study enrolled 6 participants as planned to test a schedule of a study drug called elotuzumab 
given by IV infusion once weekly for 4 weeks (total of 4 doses). An oral corticosteroid 
(Prednisone) taper was started at the time of the first dose and was finished in 10 weeks. A safety 
review was conducted when the 6th person finished his/her infusions and Prednisone taper. No 
safety concerns were identified. We  are moving to Part 1B. In this part 6 additional participants 
will be enrolled and given a different schedule of IV Elotuzumab, which will be administered as 
an infusion every 2 months for a total of 6 doses. The Prednisone taper will be given the same 
way as in Part 1A.  
 
The purpose of the more spread- out doses is to continue to evaluate safety of the study drug 
while looking at its durability (long term effect) on IgG4-RD. You will be in the study for about 
1- year from the time you join. During this time, we will ask you to visit the study site about 
once a month (16 visits). Some of these visits will be to administer the study drug. At all of the 
visits we will evaluate your overall health and IgG4-RD status.   
 
If no safety concerns are seen, a larger Part 2 study is planned to look at elotuzumab effects in 
IgG4-RD. 
 
The study is supported in part by a grant from the National Institute of Allergy and Infectious 
Diseases, of the National Institutes of Health (NIAID, NIH). Bristol-Myers Squibb Company 
(BMS) is the pharmaceutical manufacturer of elotuzumab providing the drug. 
 
Who will take part in this research? 
About 6 participants will be entered in Part 1B of the study at one of approximately 3 centers in 
the U.S. with experience in treating IgG4-RD.  
 


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What will happen in this research study? 
 
During the study, you will participate in the following: 
•  Screening phase to see if you meet the requirements to participate. 
• Treatment phase where you will receive the 12-month dosing schedule. We will also 
evaluate the safety of the study drug and your IgG4-RD with visits scheduled about once 
a month until the end of the study. 
 
Background Medications and Vaccinations: 
These are drugs that will be given during the study in addition to the investigational drug. 
 
Immunosuppressive Drugs: 
You will take oral prednisone at the beginning of the study that will be tapered off by 10 weeks 
after your first dose of elotuzumab.  Depending on your disease status at the time you enter the 
study you may be started on up to 60 mg prednisone daily during the screening period. The dose 
will need to be decreased to 40 mg or 30 mg prednisone /day (depending on the dose you are 
taking if any) by the time you start the elotuzumab, which your study physician will manage with 
you. You should never abruptly stop or try to manage your prednisone taper on your own. If you 
have already been on prednisone 40 mg/day for at least two weeks during the screening period, 
then your prednisone dose will be 30 mg/day on the day of your first elotuzumab infusion.  
 
The study will supply the daily oral prednisone beginning on the day of your first elotuzumab 
infusion through the end of the taper 10 weeks later. 
 
If you are taking drugs other than corticosteroids (prednisone) to treat your IgG4-RD, you will be 
asked to taper off those medications during the screening period. It is possible that your IgG4-
RD symptoms may worsen during this period. If screening procedures show that you fit all study 
criteria you will return to begin study treatment. 
 
Prophylaxis for SARS-CoV-2 per CDC Guidelines: 
If you agree to participate you may receive medicines to help prevent SARS-CoV-2 if available 
and recommended by CDCat the time you enter the study.  
 
Prophylaxis recommendations are subject to change over time depending on the state of the 
pandemic and prominent strain(s) of the virus. Your study doctor will inform you of the most up 
to date NIH/CDC recommendations. 
(https://www.covid19treatmentguidelines.nih.gov/overview/prevention-of-sars-cov-2/) 
 
Vaccinations: 
Vaccination against the SARS-CoV-2 virus is required to participate in this study. Vaccination 
status must conform to CDC recommendations for immunocompromised individuals. 
Vaccination must have been completed at least 2 weeks prior to start of study therapy. These 


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recommendations are subject to change but are updated at: 
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html. 
It is also recommended that you be up to date on receipt of other vaccinations to prevent 
infection before coming into the study. This includes the varicella zoster (Shingles) vaccine, the 
influenza (flu) vaccine, and the pneumonia vaccine.    
 
If you have questions, your study doctor will discuss this with you. 
 
Screening Phase 
Once you have signed the consent form, you will have a screening evaluation. A full medical 
history will be taken including the medications you take. This includes your routine cancer 
screening history. The screening evaluations are: 
 
• Complete Physical Exam: including height, weight and vital signs-temperature, blood 
pressure, heart rate, and breathing rate. 
• Routine Blood Tests: about 2 tablespoons of blood and a urine sample are collected to 
evaluate your disease status and overall health. This includes infectious disease testing 
for HIV, tuberculosis, and hepatitis. A pregnancy test is done for women able to become 
pregnant. 
o Research Blood Tests: an additional 2 tablespoons of blood are drawn for studies 
to look at your immune system and the effect of the study drug. We will collect a 
urine sample to test for your general health. 
 
• Imaging Studies: A Computed Tomography (CT) scan is obtained to evaluate the organs 
affected by your IgG4-RD. This involves a series of detailed x-ray pictures while lying 
on a table. 
o If you have had a recent CT scan, then Magnetic Resonance Imaging (MRI) may 
be substituted prior to treatment to limit your radiation exposure. MRI is a 
noninvasive test that uses a magnet to show detailed pictures of your organs. You 
lay on a table that moves into the cylinder-shaped tube where the pictures are 
taken. You are not exposed to x-rays for this. The MRI makes loud banging 
noises as it takes pictures. You are given earplugs or headphones and the 
technician can see, hear, and talk with you during the test. 
o Just before these procedures you may be given a substance called a contrast agent 
by injection into a vein. The contrast agent makes it easier to see different 
structures inside your body 
• Optional Salivary Gland biopsy (MGH participants only* Described later) 
 
The screening visit takes about 2 hours plus the time for radiology imaging studies which may be 
done on a different day. Procedures may be scheduled over more than one visit within a 1-month 
period. 
 
(CT) Computed Tomography scan 


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Computerized tomography (CT) may be done. Just before these procedures, you may be given a 
substance called a contrast agent by injection into a vein. The contrast agent makes it easier to 
see different structures inside your body. Ultrasound may be done in subjects with abnormalities 
of the liver and/or pancreas.  
 
(MRI) Magnetic resonance imaging  
MRI (magnetic resonance imaging) is a test that uses special equipment to take detailed pictures 
of body tissues and organs. During an MRI, you will lie very still, because any movement may 
make the pictures blurry, and the study doctor will not be able to interpret and understand the 
pictures. The MRI may also require a contrast agent injection to make it easier to see different 
structures inside your body. 
 
Optional Submandibular gland (MGH only) 
An optional submandibular gland biopsy will be performed between screening and Baseline Day 
0 and between Weeks 40 and 44 to assess the tissue response to study treatment. The subject will 
be instructed to stop aspirin or NSAID (medicines that are widely used to relieve pain, reduce 
inflammation, and bring down a high temperature) medication 3-7 days before the procedure. A 
local pain-killing medicine (anesthetic) may be injected, and a needle is inserted into the gland. 
A piece of tissue or cells are removed and placed on slides. An ice pack is then placed on the 
skin in the area of the biopsy to reduce swelling and bruising.  
 
Dr. Ambrose Huang, from Interventional Radiology at MGH, will perform the submandibular 
gland biopsies. 
 
I agree to participation in optional submandibular gland biopsy. 
 YES    NO   Initial ______________ 
 
After the results of the screening tests are available, the study doctor will determine if you 
qualify for this study. If you don’t qualify, your study doctor will explain the other options that 
are available to manage your IgG4-RD. 
 
Treatment Phase 
You will be given a COVID-19 antigen self-test to take at home within 24 hours of each study 
drug infusion visit. This test is a nasal swab using a Q-Tip to swab the lining of both nostrils. 
Taking the test and getting the results takes about 15 minutes. You will be given clear 
instructions on how to perform the test and how to report the results.  
 
Baseline Visit (Visit 2)  
 
If you qualify, you will return to the clinic to get your first IV dose of study drug. The study staff 
will discuss with you when the study treatment visits will occur.  
 
Visit 2 will take about one hour. At this visit, we will: 


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• You will have your medical history and the list of medications that you take updated. 
• You will be asked to report possible side effects. 
• You will have vital signs taken including height and weight 
• Physical Exam: a brief physical exam at each visit 
• Draw a blood sample 
o Safety Blood and Urine Tests: about 1½ teaspoons of blood will be drawn at each 
visit to look at your disease status and overall health 
o Research Blood Tests: an additional 2 tablespoons of blood are drawn for studies 
to look at your immune system and the effect of the study drug. Ask you for a 
urine sample for general health. 
• Urine test for pregnancy, if you are a female who can become pregnant  
• You will be asked to complete questionnaires and paper scale of disease activity  
 
 
 
Premedication 
 
Before every dose all participants will receive pre-medications to help prevent an infusion 
reaction to the study drug while and just after it is given IV. These pre-medications are:  
• an IV corticosteroid,  
• famotidine (Pepcid® or equivalent) oral or IV,  
• diphenhydramine (Benadryl® or equivalent) oral or IV,  
• and an oral anti-fever medication (Tylenol®, acetaminophen).  
 
Taking the Study Drug 
 
We have completed Part 1A of the study. In Part 1B, you will receive one elotuzumab infusion 
every 2 months for a total of 6 doses.  
 
You are admitted to the infusion center on the mornings of each scheduled dose. After 
completion of the pre-infusion procedures (described below) you will have an IV catheter (thin, 
plastic tube) inserted in a vein in your arm or hand. Each dose of study drug is given over about 
2 hours, and you are closely monitored for safety during and after the infusion. You should plan 
to be in the infusion center for approximately 4-6 hours on each of the infusion days.  
Prednisone Taper  
 
On the first infusion day, you will begin taking prednisone every day for a 10- week taper. You 
will start at 40 mg prednisone/day unless you have already been taking this dose for at least 2 
weeks prior. If so, you may begin the taper at prednisone 30 mg/day. This will be provided by 
the study in bottles with clear instructions for how to taper the dose. You are asked to bring your 


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bottles back to each study visit. Each dose is in a different bottle with a different color capsule. 
You will be given multiple bottles with clear instructions on when to start and stop each bottle. 
There will be extra capsules in each bottle to return at your next scheduled study visit. Site study 
staff will explain how to take the prednisone in a decreasing dose over the next 10 weeks until 
you have finished the taper and are taking no more. Please do not take your morning dose on the 
day of any study visit, as you will take that day’s dose from the new bottle given to you.  
 
Part 1B Treatment Phase  
 
The study visits are scheduled about monthly, with the study drug administered every 2 months 
for 6 doses. You will visit the study site for safety checks where you don’t receive the study drug 
in between. A phone/virtual visit will be conducted about 7 days after your 1st infusion to see 
how you are doing. If thought necessary for your safety/well-being you may be asked to come in 
for an unscheduled visit. For the 12-month treatment schedule the infusions happen at Week 0 
(1st dosing visit), and again at Weeks 8, 16, 24, 32, & 40)  
The final study visits for safety and status of your IgG4-RD happen at Weeks 44 and 48 (about 
one year after starting). 
 
Each In person Visit 
 
At each visit during this part of the study, the following will happen:  
• We will review your medications  
• You will be asked to report possible side effects. 
• You will have vital signs taken including height and weight 
• You may have a physical examination by the study doctor 
• Safety Blood and Urine Tests: About 1½ teaspoons will be drawn for this health check at 
the safety visits and within 48-72 hours of each study drug infusion visit.  
 
Most Visits 
At most visits, we will also obtain/perform:  
• A brief physical exam at each visit except for the Week 24 and 48 visits, when you have 
a complete physical exam. 
• You will be given a COVID-19 antigen self-test to take at home within 24 hours of each 
study drug infusion visit. This test is a nasal swab using a Q-Tip to swab the lining of 
both nostrils. Taking the test and getting the results takes about 15 minutes. You will be 
given clear instructions on how to perform the test and how to report the results. (Wks. 8, 
16, 24, 32, & 40)  
• Urine test for pregnancy if you are a female who can become pregnant (Wks. 8, 16, 24, 
32, & 40) 
• Draw a blood research blood test: an additional 2 tablespoons of blood are drawn for 
studies to look at your immune system and the effect of the study drug (approximately 
every 2 months). 


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• Ask you for a urine sample for general health ((3 times during the study) 
• Premedication and study drug infusion (Wks. 8, 16, 24, 32, & 40) 
• You will be asked to complete questionnaires and paper scale of disease activity 
  
Some Visits 
At some visits, we will:  
• Complete physical exam (Wks. 24 & 48) 
• Obtain imaging Studies: CT scan or MRI is repeated to evaluate the organs affected by 
your IgG4-RD at the Week 48visit. The follow-up visits should take about one hour, 
except for the Week 48 visit which can take 3-4 hours, depending on time needed for 
CT/MRI 
• Review prednisone taper (Wks. 1(by phone), 4, 8, &12) 
Extra or unplanned visits 
 
You may be asked to return to the study site in-between the visits described above if your study 
doctor thinks it important for your safety. 
 
After You Complete the Study 
After you complete the study, we will refer you back to your own doctor for your ongoing 
medical care.  
 
Stopping the Study Early 
 
You may have study drug discontinued without your consent at any time. Reasons why this 
could happen include, but are not limited to, the following: 
• Your study doctor decides that it is best for you not to continue. 
• You are unable to complete study tests. 
• The study is stopped by the Institution, the Sponsor(s), or other health authorities. 
• You become pregnant or plan to get pregnant during this study. 
• You have severe side effects from elotuzumab. 
• You need medications that are not allowed for this study. 
• Your disease gets worse in the kidney or in other organs. 
 
If study drug is discontinued early, we would like for you to continue all follow-up visits through 
one year. Otherwise, we would like to see you for a study discontinuation visit which will 
include all assessments listed for the Week 48 visit. 
 
 
How may we use and share your samples and health information for 
other research?
 
Health Information 


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Your medical and research records will be confidential to the extent permitted by law. Every 
effort is made to keep your identity private. However, we cannot guarantee complete 
confidentiality.  
 
You will be identified by a study code, not your name. Personal information from your records 
will not be released without your written permission. You will not be identified in any 
publication or in the sharing of your data about this study. After the study is completed, this 
study data may be placed in a central storage location. These data will not include your name or 
other information that can identify you. The purpose is to make study data available to other 
researchers. Information from this study may be put into databases along with information from 
other studies. There are different kinds of databases; some are publicly accessible, and some are 
restricted. Only researchers who apply and are approved can access restricted databases. 
Traditionally used identifying information about you (such as name, address, medical record #, 
etc.) will NOT be included or shared with others.  
 
In an NIH funded study, you are further protected through a policy that prevents the study doctor 
from releasing any sensitive information about you that may identify you. This would not 
prevent you or a family member from voluntarily releasing information about this research.  
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:  
o The National Institute of Allergy and Infectious Diseases (NIAID, NIH), sponsor of this 
research;  
o NIAID representatives, agents, employees, contractors, grantees and other persons 
assisting in the conduct, monitoring, or analysis of this study;  
o Representatives of Bristol-Myers Squibb, Co., the pharmaceutical partner providing the 
study drug  
o The U.S. Food and Drug Administration (FDA);  
o Other state and local health and/or regulatory authorities.  
 
These organizations and agencies may also ask permission to look at your medical records from 
other doctors, hospitals, or other healthcare providers.  
 
After the study is completed, the data are placed in a central storage location, or public database. 
This includes all the information learned from this study and not just information about you. The 
reason is to share data with other researchers. All data is coded and will not be linked with your 
name or other identifying information such as social security number or birthday. 
 
 
OPTIONAL STORAGE OF LEFTOVER BLOOD SAMPLES FOR FUTURE USE 
 
We would like to ask your permission to store any left-over blood from the samples collected to 
be used in the future to study the immune system, IgG4-RD, and other diseases. Since we do not 
yet know the exact questions that will be studied, we cannot tell you exactly what tests will be 


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done on your samples. As a research participant in this study, you have the option of allowing 
any leftover blood samples to be stored for future tests. Samples will be stored at the Ragon 
Institute of MGH, MIT and Harvard, and at Emory University. We plan to store your samples for 
an unknown length of time. 
 
We may want to share your samples with researchers at other institutions. Your samples will be 
coded with a number so that your name cannot be identified. Only the investigators of this study 
will have the code that links you to your specimens. Reports about research done with your 
samples will not be put in your medical record and will be kept confidential, to the best of our 
ability and within state and federal law. Information that does not become part of your medical 
record will be identified by a code, and personal information from your records will not be 
released without your written permission. You will not be identified in any publication about this 
study. Reports on these stored samples will not be given to you or your physician(s). Your blood 
samples will not be sold or used directly to produce commercial products. 
 
You can change your mind at any time and ask to have your samples destroyed, and we ask that 
you notify your study physician in writing if you choose to do so. If your sample(s) have not 
been used for future tests, they will be destroyed when your request is received. If your sample(s) 
have already been used prior to this request, then the information will be used in the overall 
study analysis. 
 
Benefits: There are no direct benefits to you from the collection and storage of these samples. 
The benefit of research on stored samples for society is the information that can be learned about 
the immune system and IgG4RD. You will not receive any financial gain from studies done 
using your stored samples. 
 
Risks: There may be unknown risks associated with the storage and analysis of your blood 
samples or the information resulting from the analysis of your samples. Every effort will be 
made to maintain your confidentiality. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Making a Decision: Please consider the storage of leftover blood samples for future use as 
described above and answer the question below. No matter what you decide, it will not affect 
your care or participation in this study. The choice is up to you. 
 
Please indicate your response below: 
 
I agree to the storage, future use and sharing of my samples (blood, tissue (MGH biopsies)) and 
sharing of information/data resulting from those future analyses for genetic tests not currently 
planned. 
 YES    NO   Initial ______________ 
 
I agree to the storage, future use and sharing of my samples (blood, tissue) and sharing of 
information /data resulting from those future analyses for other tests not currently planned. 
 
 YES    NO   Initial ______________ 
 
OPTIONAL FUTURE CONTACT 
 
At the completion of this research study your study doctor would like to ask your permission to 
contact you in the future related to your health and participation in this study. We may contact you 
as a follow-up to this study or we may contact you to invite you to take part in future studies related 
to IgG-4 Related Disease. Please indicate below whether you would allow future contact by us.  
 
Please initial/date your responses to the following questions below: 
 
I agree to permit my study doctor to contact me regarding future research studies related to IgG-4 
RD.    
 
 YES  
Initial ______________ 
Date: ___/___/___     
 No  
Initial ______________ 
Date: ___/___/___     
 
I agree to permit a study doctor to contact me in the future as a follow-up to my health status 
related to this study after my participation has ended.  
 
 YES  
Initial ______________ 
Date: ___/___/___     
 No  
Initial ______________ 
Date: ___/___/___     
 
Will you get the results of this research study? 
 
 Generally, we will not give you or your doctor information about the results of your 
individual participation in the research study.  The research we are doing is only a stepping- 
stone in understanding IgG4.  Most of the findings that come from studying your samples or 


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information will not be relevant to your personal health.  However, in the future, this may 
change. 
 It is important to remember that research results are not always meaningful and are not the 
same as clinical tests.  While you should not expect to get any information about the results 
of your participation in this research, if something about you is learned that would be 
important for you to know for your safety or well-being, we will attempt to contact you to let 
you know.  In some situations, follow-up testing might be needed.  in a certified clinical lab.  
You and your medical insurer will may be responsible for the costs of these follow-up tests 
and any follow-up care, including deductibles and co-payments.   
 
What are the risks and possible discomforts from being in this research 
study? 
Elotuzumab Risks 
 
Infusion Reaction  
 
The information on risks and side effects with elotuzumab from the drug manufacturer, Bristol-
Myers Squibb Company, comes from the cancer studies in multiple myeloma. There have been 
reports of infusion reactions in up to 10% of patients in the large trials, with 70% happening 
during the first dose. The most common symptoms of an infusion reaction included fever, chills, 
and low blood pressure. Other symptoms may include the following: rash, chest pain, trouble 
breathing, swelling of the throat/tongue (extremely rare allergic reaction), dizziness, light-
headedness. Most of the reactions were mild or moderate, resulting in temporary stopping of the 
infusion to treat the reaction. 1% were severe resulting in permanent discontinuation of the drug. 
While there have been no reports of life-threatening reactions, there is the potential for serious, 
life-threatening reactions including anaphylaxis (severe allergic reaction).  
 
Infusion reactions can happen during the elotuzumab infusion or within 24 hours after. Before 
every infusion, you will receive pre-medications to help lower your chances of having an 
infusion reaction. These include:  
• glucocorticoids that you will receive intravenously,  
• diphenhydramine (Benadryl®/equivalent) intravenously or orally,  
• famotidine (Pepcid® or equivalent) intravenously or orally, and  
• acetaminophen (Tylenol®/equivalent) orally.  
 
You will be monitored closely by the research team during and after the infusions who are 
trained and equipped to quickly manage a reaction. If needed the drug will be temporarily 
stopped and/or the rate slowed down.  
 
Other Frequently reported Adverse Events 
• fatigue 
• numbness 


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• weakness 
• tingling 
• burning pain in your arms or legs 
• diarrhea 
• sore throat or runny nose 
• fever 
• upper respiratory tract infection 
• constipation 
• decreased appetite 
• cough 
• pneumonia 
 
Infection  
 
Infections have been reported in the cancer studies occurring in most patients. Some of these 
infections were severe or life-threatening resulting in hospitalization. Fatal infections were rare. 
The most common serious infections were pneumonia and respiratory tract infections. Other 
unusual infections reported included fungal infections (10%), and herpes zoster (17%).  
Make sure you contact your study doctor and seek medical care right away if you have any signs 
and symptoms of an infection, including fever, flu-like symptoms, sore throat, cough, shortness 
of breath, burning with urination, a painful skin rash, or other.  
 
Before coming into the study you are encouraged to be up-to-date on recommended vaccinations 
to prevent infection, including the varicella zoster (Shingles) vaccine. Your study doctor will 
discuss this with you if you have questions.  
 
Liver Damage (Hepatotoxicity) 
  
One of the large cancer studies reported increases in liver function blood tests in small numbers 
of people. Some resulted in discontinuation of treatment, but most did not.  
 
In this study you will be monitored closely with frequent blood tests to check your liver. The 
elotuzumab may be discontinued if needed for your safety. Inform your study doctor and seek 
medical care right away if you have signs and symptoms of liver problems including tiredness, 
weakness, loss of appetite, yellowing of your eyes or skin, color changes in your stools, 
confusion, or swelling of the stomach area.  
 
Cancer (Malignancy)  
 
Studies with the drug have been in cancer (multiple myeloma). There are no reports showing  
safety concerns of development of new cancers in these trials. As a precaution, this study  
will not enroll people who had cancer in the past 5 years (except for successful treatment  


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(excision) of cervical and non-myeloma skin cancer). If over the age of 50 (and earlier if you 
have risk factors) you should have age-appropriate cancer screenings prior to participating and 
throughout the study. Inform your study doctor and health care provider right away for any 
warning signs of cancer. More information may be found on the American Cancer Society 
website: http://www.cancer.org/healthy/find-cancer-early/cancer-screening- guidelines.html 
 
There may be unanticipated risks which we are not yet aware of. You will be informed of any  
new risk information as we learn of it. 
 
There may be other unknown risks from taking elotuzumab that we do not know about yet. 
 
Corticosteroid/prednisone Risks 
 
Common side effects of corticosteroids used for a daily tapering dose as we will prescribe  
include glucose intolerance/diabetes, hypertension, osteoporosis (thinning of bones), increased  
risk of infection, glaucoma, cataracts, weight gain, moon face, acne, thin skin, mood swings, and  
irritability. The risk of the more permanent effects increases with chronic, longer-term use. 
 
Pre- Medication Risks 
 
Risks of the pre-medications administered to decrease the risk of study drug infusion reaction are  
listed in the table below. The corticosteroid side effects described above related to daily dosing  
do not all apply to the single doses given as pre-medication. Those more short-term effects are  
described below. 
• Corticosteroids/glucocorticoids: Mood swings, hot flashes, insomnia 
• famotidine (Pepcid® or equivalent): Headache, constipation, nausea, vomiting, diarrhea 
• acetaminophen (Tylenol/equivalent): Rash, nausea, headache; very rarely: 
hypersensitivity (allergic reaction), serious skin reactions, kidney/liver damage with high 
doses or drug/alcohol interactions 
• diphenhydramine (Benadryl/equivalent): Somnolence (drowsiness), difficulty 
concentrating, dry mouth, difficulty urinating, constipation 
 
Study Procedure Risks 
 
Blood Drawing Risks 
 
Possible side effects from having blood drawn include dizziness, redness and swelling of the  
vein, pain, bruising, or bleeding from the site of the needle puncture. There is also a chance of  
infection. 
 
 
 
 


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Blood collection during study: 
The following table shows the amount of blood that will be taken from you at each visit  
Visits  
Amount of blood withdrawn  
Screening 
Approximately 27 mL (about 2 tablespoons) 
Baseline 
Approximately 78 mL (about 5 tablespoons) 
Weeks 4, 12, 20, 28, 36, 44 
Approximately 7 mL (about 1½ teaspoons) 
Weeks 8, 16, 24, 32, 40, & 48 
Approximately 57 mL (about 4 tablespoons) 
IV Catheter Risks 
 
The risks for this procedure are rare and often mild. They include minor discomfort, bleeding,  
and bruising at the needle site. These symptoms often get better without medical help. You may  
also have some restriction of movement during the infusion time. Infection (indicated by redness,  
warmth, pain, swelling, and foul-smelling discharge) at the needle site can rarely occur. 
 
Optional Submandibular Gland Biopsy 
Risks from this procedure may include: 
• Allergic reaction to the anesthetic 
• Bleeding 
• Infection 
• Injury to the facial or trigeminal nerve (rare) 
• Numbness of the lip 
 
Radiation Risks 
 
CT (Computerized Tomography) Scan: As a result of your participation in this study you may be 
exposed to radiation from up to 2 CT scans. If you take part in this research protocol, you may 
undergo CT scans during screening involving ionizing radiation. These would not be needed for 
clinical care if you were not in the research study. The type and body parts included in the 
imaging studies will depend on your diagnosis.  In general, exposure to ionizing radiation may 
have health risks. In clinical imaging studies the benefits to individual normally overweigh risks. 
In research studies the benefits are normally to future groups or population and may not be to the 
individual. 
  
You will be exposed to a maximum of approximately 24 millisieverts (mSv) for this research. A 
mSv is a unit of radiation dose. This amount of radiation is about the same as you would 
normally get in about 8 years from natural background sources from the earth and the sky. 


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The radiation doses used in this study could cause a small increase in the risk of developing 
cancer later in life. We always try to use the smallest possible radiation dose needed to get the 
imaging information we need. If you are pregnant or breastfeeding, you will not be able to 
participate in this research study.  
 
Since the effects of radiation can add up over time, it is important that you tell the study doctor 
about your past clinical imaging and research-related radiation exposure. If you have taken part 
in other research studies in the past 12 months that have involved radiation exposure, please tell 
us. If it appears that your earlier radiation exposure is more than our current guidelines, it is 
possible that you will not be allowed to participate in this study. Please initial next to your choice 
below: 
 
            I have participated in other research studies (not including this study) involving radiation 
exposure within the last 12 months. 
  
            I have not participated in other research studies (not including this study) involving 
radiation exposure within the last 12 months. 
  
CT Contrast Risks:   
It is possible that you may receive contrast material (dye like iodine) intravenously or barium to 
swallow for the CT scans. Contrast material may rarely cause an allergic reaction, or very rarely 
serious reaction (anaphylaxis). Let the study doctor know if you are allergic to shellfish or iodine 
or have had a reaction to contrast dye in the past. Contrast material can harm to the kidneys, 
particularly in people with kidney disease. If you have kidney disease related to your IgG4-RD 
or other cause, then use of contrast material may not be an option.  
 
Risk of MRI Scans: MRIs use powerful magnets to make images.  There are no known radiation 
risks associated with MRI.  However, persons with metal implants, such as surgical clips, or 
pacemakers should not have an MRI.  All credit cards and other items with magnetic strips 
should also be kept out of the MRI room.  People who feel uncomfortable in confined spaces 
(claustrophobia) may feel uncomfortable in the narrow tube.  The MRI makes loud banging 
noises as it takes images.  Earplugs can be used to reduce the noises.  The MRI can be stopped at 
any time at your request.  If you are or suspect you are pregnant, you should not participate in 
this study.   The MRI has the potential, during normal routine use, to cause localized warming of 
your skin and the underlying tissues.  You should immediately inform us if you experience 
discomfort due to warming and the procedure will be stopped.   
  
Some people experience dizziness or rarely nausea when going into an MRI scanner and these 
sensations may be more common in scans with higher magnetic fields. In most cases, these 
symptoms only last a short time. However, some people may experience them throughout the 
scan and/or continue to experience them for a short period of time after; generally, less than half 
an hour. No case of permanent problems is known. 


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Gadolinium contrast Risks 
 
No all subjects will receive gadolinium in this study. A few patients will report a cold feeling in 
the arm during the injection, which is of no significance. An even smaller number (between 
about 1 and 4 in 100) will notice mild nausea or headache. Vomiting can occur, but this is rare 
(less than 1 in 100 injections). Even less often, in approximately 1 in 1000 patients, an itchy skin 
rash might appear a few minutes after the injection. This appears to be due to a mild allergy. It 
usually settles down by itself within an hour or so, but rarely it might be a warning sign of a 
more serious allergic reaction developing. 
 
Severe allergic (anaphylactic) reactions to gadolinium are rare. These severe reactions, which 
might involve difficulty breathing and swelling of the lips and mouth, occur in approximately 1 
in every 10,000 people who have gadolinium. These severe reactions generally respond very 
well to standard emergency drug treatment, like that given for other severe allergic reactions. 
These are usually medications that will be given through the tube that was placed in your arm 
before or during the MRI scan. 
 
Vaccine Risks 
Both elotuzumab and corticosteroids blunt (decrease) your immune system’s response which 
may decrease the amount of protection you receive from vaccines. For this reason, certain 
vaccines, including booster with the COVID-19 vaccine, must occur at least 2 weeks before 
receiving the first dose of study drug. This study drug may also increase your risk of infection 
after receiving a live vaccine (for example: mumps, measles, and rubella). You should not 
receive any live vaccinations for at least 30 days before you enter the study and for at least 3 
months after your last dose of study drug.  
 
We advise you to be up to date with all recommended vaccines at least 2 weeks before enrolling 
in this study.  
 
Incidental Findings  
If during the study testing, unexpected (non-study-related) information is learned that would be 
important for you to know for your well-being, you will be informed. This includes findings 
from the radiology (CT or MRI) tests. Counseling will be provided on next steps to take. The 
study will not cover costs for related follow-up outside of the study. 
 
Information related to COVID-19 
• Immunization with one of the FDA authorized or licensed SARS-CoV-2 vaccines is 
required for study entry. Vaccination series must have been completed at least 2 weeks 
prior to start of study therapy.  
• Both elotuzumab and corticosteroids suppress your immune system and may increase 
your susceptibility to getting a COVID-19 infection. Also, infection could be more severe 
as a result of receiving these drugs. This is true with any infection when taking drugs that 


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suppress the immune system. These drugs may also interfere with the amount of 
protection you receive from a COVID-19 vaccination. 
• The COVID-19 public health emergency changed the study.  Enrollment in the study was 
closed temporarily while safety measures were added to the protocol. Visits were 
conducted remotely or virtually in some cases.  Changes were made to how the study was 
conducted. Though the pandemic is considered over, safety measures related to COVID-
19 remain in place. 
• Measures to protect yourself and others from COVID-19 infection are outlined on the 
Centers for Disease Control website at the following link: 
https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. To 
decrease your risk of infection with SARS-CoV-2, we strongly recommend that you 
follow these recommendations, which include wearing a mask, practicing social 
distancing, and frequent handwashing/use of hand sanitizer. 
If you develop COVID-19 infection during your participation in the study, the infusions of 
elotuzumab will be suspended until you have recovered from the infection.  
 
Risks to an Embryo or Fetus, or to a Breastfeeding Infant 
The risks to a developing fetus or breast-feeding infant are unknown with this drug. You cannot  
participate in this study if you are pregnant, breastfeeding or planning a pregnancy while in the  
study. 
 
Female participants of childbearing potential and male participants with a partner of childbearing  
potential must agree to use a highly effective method of contraception throughout the study, for 6 
months after the last infusion of elotuzumab. Highly effective methods are defined as those, 
alone or in combination, with a low failure rate (i.e. less than 1 percent pregnancy per year) when 
used consistently and correctly. Options include implant or intrauterine device (IUD), other 
hormonal method (injectable, oral, transdermal) with barrier method, or double barrier method. If 
you leave the study early, you must use contraceptive methods for at least 6 months after your 
last dose of study drug. If you are a woman able to become pregnant, we will perform pregnancy 
testing throughout the study. You will be asked about your reproductive potential and 
contraceptive use at each visit.  
 
If you should become pregnant while in this study, or if you think your partner is pregnant (male 
participant), you must contact a study doctor right away. If you are female and still receiving the 
study drug, the doctor will stop it and you will continue to be followed until the baby is born or 
the pregnancy is ended. 
 
What are the possible benefits from being in this research study? 
 
There are no direct benefits to you to be in this study. What is learned from the study may benefit 
society and help others with IgG4-RD in the future. 
 
 


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What other treatments or procedures are available for your condition? 
 
You do not have to take part in this research study to be treated for IgG4-RD. There is currently 
no cure for IgG4-RD. However, there are medications, such as corticosteroids/glucocorticoids 
(prednisone) available to manage some symptoms of IgG4-RD. Alternative options that may be 
available to you include treatment with other medicines such as rituximab. 
 
Talk with your study doctor if you have questions about any of these treatments. 
 
You will be informed of any new findings from this or other research that may affect your 
willingness to continue in this study. 
 
If, during the study testing, unexpected (not study-related) information is learned that would be 
important for you to know for your well-being, you will be informed of that information. 
Counseling will be provided as to next steps. The study will not cover costs for related follow-
up.
Can you still get medical care within [insert site name] if you don’t take 
part in this research study, or if you stop taking part? 
 
Yes.  Your decision won’t change the medical care you get within [insert site name] now or in 
the future.  There will be no penalty, and you won’t lose any benefits you receive now or have a 
right to receive. 
 
We will tell you if we learn new information that could make you change your mind about taking 
part in this research study. 
 
 
What should you do if you want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed. 
 


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Will you be paid to take part in this research study?
 
For part 1, you will be paid $1,500.00 if you complete the study.  If you do not complete the 
study, we will pay you $125 for each infusion visit and $75 for non-infusion visits you complete.   
Visit 
Stipend 
Infusion visits (6) 
$750.00 
Non-Infusion visits (10) 
750.00 
 
We may use your samples and information to develop a new product or medical test to be sold.  
The Sponsor, hospital, and researchers may benefit if this happens.  There are no plans to pay 
you if your samples or information are used for this purpose. 
 
We may be using an approved, outside vendor (Forte Research to make these payments to you 
via a reloadable credit card-based system, called Forte Payments. This secure system is like a gift 
card or credit card.  
 
If you are paid by this system, you will be given a Forte Payments Visa card when you enroll in 
the study. Once the card is activated, the study team will add a payment after each paid visit you 
complete. The payment should be available to you within a day. You may use the card anywhere 
Visa cards are accepted, such as at a grocery store.   
 
All reasonable expenses related to travel to and from the study site including lodging, meals, and 
transportation will be reimbursed. Participating patients and/or families will need to provide 
receipts for travel reimbursement.  
 
Part 1 B: All visits outlined in consent form 
• Up to the government’s per diem lodging rate for your area (see 
http://www.gsa.gov/portal/category/100120 for details) 
o A second day/night may be charged for Screening, Day 0, weeks 4, 8, 16, 24, 32, 
and 40Up to the government’s per diem meals rate for your area (see 
http://www.gsa.gov/portal/category/100120 for details) 
 A second day/night may be charged for Screening, Day 0, weeks 4, 8, 16, 
24, 32, and 40Up to $50/visit for transportation for subjects who live 121-
300 miles away → $450 / subject 
 Up to $600/visit for airfare for subjects who live more than 300 miles 
away → $5,400 / subject 
 


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We will need to collect your Social Security number in order to make these payments, and it will 
be shared securely with the company that runs the card-based system.  Payments like this are 
considered taxable income.  If you receive more than $600, the payment will be reported to the 
IRS as income by the hospital. If you provide a receipt for something like travel expenses and we 
can cover that, that is not considered taxable income.  Reimbursement of expenses will not be 
made using the Forte Payments card. 
 
What will you have to pay for if you take part in this research study? 
 
Costs related to usual clinical care of your IgG4-RD or other medical problems will be billed to 
you and/or your insurance provider(s). The study drug, elotuzumab, is being provided by the 
manufacturer, Bristol-Myers Squibb, Co. The study is providing the pre-medications for the 
infusions and steroid tablets for the prednisone taper. Other clinical and professional services 
including diagnostic and laboratory tests that are a part of this study and not part of your regular 
care will be covered by the study. 
What happens if you are injured as a result of taking part in this 
research study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the beginning of this consent form. 
 
If you take part in this research study, how will we protect your privacy? 
 
Federal law requires Mass General Brigham to protect the privacy of health information and 
related information that identifies you.  We refer to this information as “identifiable 
information.” 
 
In this study, we may collect identifiable information about you from: 
• Past, present, and future medical records 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Informed Consent Template 
 
 
 
 
AIG01 Part 1 Informed Consent Template 
 
Page 24 of 26 
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• Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable information and why: 
• Mass General Brigham researchers and staff involved in this study 
• The sponsor(s) of the study, and people or groups it hires to help perform this research or 
to audit the research 
• Other researchers and medical centers that are part of this study 
• The Mass General Brigham ethics board or an ethics board outside Mass General 
Brigham that oversees the research 
• A group that oversees the data (study information) and safety of this study 
• Non-research staff within Mass General Brigham who need identifiable information to do 
their jobs, such as for treatment, payment (billing), or hospital operations (such as 
assessing the quality of care or research) 
• People or groups that we hire to do certain work for us, such as data storage companies, 
accreditors, insurers, and lawyers 
• Federal agencies (such as the U.S. Department of Health and Human Services (DHHS) 
and agencies within DHHS like the Food and Drug Administration, the National 
Institutes of Health, and the Office for Human Research Protections), state agencies, and 
foreign government bodies that oversee, evaluate, and audit research, which may include 
inspection of your records 
• Public health and safety authorities, if we learn information that could mean harm to you 
or others (such as to make required reports about communicable diseases or about child 
or elder abuse) 
• Other researchers within or outside Mass General Brigham, for use in other research as 
allowed by law. 
 
Certificate of Confidentiality 
 
A federal Certificate of Confidentiality (Certificate) has been issued for this research to add 
special protection for information and specimens that may identify you.  With a Certificate, 
unless you give permission (such as in this form) and except as described above, the researchers 
are not allowed to share your identifiable information or identifiable specimens, including for a 
court order or subpoena.  
 
Certain information from the research will be put into your medical record and will not be 
covered by the Certificate.  This includes records of medical tests or procedures done at the 
hospitals and clinics, and information that treating health care providers may need to care for 
you.  Please ask your study doctor if you have any questions about what information will be 
included in your medical record.  Other researchers receiving your identifiable information or 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Informed Consent Template 
 
 
 
 
AIG01 Part 1 Informed Consent Template 
 
Page 25 of 26 
Version 4.0 May 19, 2023 
specimens are expected to comply with the privacy protections of the Certificate.  The Certificate 
does not stop you from voluntarily releasing information about yourself or your participation in 
this study. 
 
Even with these measures to protect your privacy, once your identifiable information is shared 
outside Mass General Brigham, we cannot control all the ways that others use or share it and 
cannot promise that it will remain completely private.  
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your identifiable information.  Your permission to use and share 
your identifiable information does not expire.   
 
The results of this research may be published in a medical book or journal or used to teach 
others.  However, your name or other identifiable information will not be used for these 
purposes without your specific permission. 
 
Your Privacy Rights 
 
You have the right not to sign this form that allows us to use and share your identifiable 
information for research; however, if you don’t sign it, you can’t take part in this research study. 
 
You have the right to withdraw your permission for us to use or share your identifiable 
information for this research study.  If you want to withdraw your permission, you must notify 
the person in charge of this research study in writing.  Once permission is withdrawn, you cannot 
continue to take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others, and such information may continue to be used for certain 
purposes, such as to comply with the law or maintain the reliability of the study. 
 
You have the right to see and get a copy of your identifiable information that is used or shared 
for treatment or for payment.  To ask for this information, please contact the person in charge of 
this research study.  You may only get such information after the research is finished. 
 
 
 
 
 
 
 
 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Informed Consent Template 
 
 
 
 
AIG01 Part 1 Informed Consent Template 
 
Page 26 of 26 
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Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
 I have read this consent form. 
 This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
 I have had the opportunity to ask questions. 
 I understand the information given to me. 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my identifiable 
information to be used and shared as described above. 
 
 
 
 
 
 
Subject 
Date 
Time  
 
Signature of Study Doctor or Person Obtaining Consent: 
 
Statement of Study Doctor or Person Obtaining Consent 
 
 I have explained the research to the study subject. 
 I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date 
Time  
 
Consent Form Version Date:       
 

Prot_SAP_002.pdf: 




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Protocol Synopsis 
Title 
Elotuzumab in IgG4-Related Disease 
Clinical Phase 
II 
Number of Sites 
Part 1: approximately 3 
Part 2: approximately 10 
IND Sponsor/Number 
DAIT/NIAID, NIH / IND# 147042 
Study Objectives 
Primary Objectives 
Part 1: To determine the safety and tolerability of the addition of 
elotuzumab to prednisone in participants with IgG4-RD. 
Part 2: To compare the effect of the addition of elotuzumab versus 
placebo to prednisone on the IgG4-RD RI at 48 weeks in participants with 
IgG4-RD. 
Secondary Objectives 
1. To compare the effect of the addition of elotuzumab versus placebo 
to prednisone on complete remission at 48 weeks. 
2. To compare the effect of the addition of elotuzumab versus placebo 
to prednisone on the number of disease flares (as defined in Section 
3.5.3) per participant over time.   
3. To compare the effect of the addition of elotuzumab versus placebo 
to prednisone on the change from baseline in Physician Global 
Assessment (PhGA) at 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 
weeks. 
4. To compare the effect of the addition of elotuzumab versus placebo 
to prednisone on Patient Global Assessment (PGA) at 4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 44, and 48 weeks. 
5. To compare the effect of the addition of elotuzumab versus placebo 
to prednisone on safety. 
 
Exploratory Objectives 
1. To compare the effect of the addition of elotuzumab versus placebo 
to prednisone on serum immunoglobulin levels, IgG subclass 
concentrations, IgE levels, eosinophils, and serum C3 and C4 levels. 


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2. To compare the effect of the addition of elotuzumab versus placebo 
to prednisone on participants’ ELF scores.  
3. To evaluate the effect of elotuzumab on CD4+ T cells and B cell 
subsets, specifically:  
a. CD4+ cytotoxic T lymphocytes 
b. CD8+ cytotoxic T lymphocytes 
c. CD4+ T follicular helper cells 
d. CD4+ peripheral helper T cells 
e. Plasmablasts 
f. Activated B cells, including double-negative (CD19+IgD-CD27-) B 
cells 
4. To determine the kinetics of cell depletion induced by elotuzumab 
on disease-associated, SLAMF7-expressing lymphocyte 
subpopulations including CD4+ cytotoxic T cells and activated B cells, 
including plasmablasts.   
5. To determine the effect of elotuzumab at the tissue level, using 
submandibular gland biopsies in participants with submandibular 
gland disease who consent separately to biopsies before and after 
treatment. 
6. To determine the utility of using the clonally-expanded effector 
subset (CD57+CD28-) of CD4+CTLs as a biomarker of disease activity. 
7. To determine the utility of soluble plasma SLAMF7 levels as 
indicators of disease activity and predictors of disease relapse.  
8. To evaluate the longitudinal profile of patient reported outcomes on 
quality of life over the study period using the SF-36 health survey. 
Study Design 
This is a two-part multi-center clinical trial in participants with active 
IgG4-RD.  Part 1 is an open-label, dose escalation phase to determine the 
safety of elotuzumab for investigation in IgG4-RD. If the addition of 
elotuzumab to prednisone is determined to be safe, Part 2 will be 
initiated as randomized, placebo-controlled, double-blinded trial. Part 2 
will compare the effects of the addition of elotuzumab versus placebo to 
prednisone in participants with IgG4-RD. Approximately 75 participants 
with active IgG4-RD will be enrolled in the overall program, 12 in Part 1 
and 63 in Part 2. 
Primary Endpoint 
Part 1: Primary Safety Endpoint 
The proportion of participants in each cohort who experience at least 
one Grade 3 or higher adverse event during study participation. 
 
Part 2: Primary Efficacy Endpoint 
Disease response at 48 weeks, defined as percent improvement in the 
IgG4-RD RI score over baseline.  
 


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Secondary Endpoints  
Part 2:  Key Secondary Efficacy Endpoint 
1. Complete remission at 48 weeks, defined as an IgG4-RD RI Score of 0 
and a glucocorticoid dose of 0 mg/day and no flare since beginning 
treatment. 
Part 1 and Part 2: Additional Secondary Efficacy Endpoints  
1. The proportion of participants that reach the following threshold 
levels of IgG4-RD RI improvement at 48 weeks:  50% and 75%. 
2. Number of disease flares, as defined in Section 3.5.3, by 24 and 48 
weeks.   
3. Change in PhGA from baseline. 
4. Change in PGA from baseline. 
5. Disease-related damage, as measured by the damage section of the 
IgG4-RD RI at 24 weeks. 
 
Part 1 and Part 2: Secondary Safety Endpoints  
1. The proportion of participants who experience at least one Grade 2 
or higher adverse event.  
2. The proportion of participants with a Grade 3 or higher infection. 
3. The proportion of participants who experience a malignancy. 
4. The proportion of participants who experience a Hepatotoxicity, 
defined as an increase in the aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) to elevations three times the upper 
limit of normal.  
5. The proportion of participants who experience a serious adverse 
event.  
6. The proportion of participants who experience infusion reactions, 
defined as any adverse reaction within 24 hours of infusion which 
are Grade 2 or higher events and at least possibly related to study 
drug. 
 
Part 2: Secondary Safety Endpoint  
1. The proportion of participants who experience at least one Grade 3 
or higher adverse event. 
  
Exploratory Endpoints 
Part 1 and 2: Exploratory Endpoints 
1. Serum immunoglobulin levels, IgG subclass concentrations, IgE 
levels, eosinophils, and serum C3 and C4 levels. 
2. ELF score (see Section 3.5.7). 
3. Blood concentrations of T cells and B cell subsets of interest, 
specifically:  
a. CD4+ cytotoxic T lymphocytes 
b. CD8+ cytotoxic T lymphocytes 
c. CD4+ T follicular helper cells 


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d. CD4+ peripheral helper T cells 
e. Plasmablasts 
f. Activated B cells, including double-negative (CD19+IgD-
CD27-) B cells 
4. Comparison of the kinetics of cell depletion induced by the addition 
of elotuzumab versus placebo to prednisone on disease-associated, 
SLAMF7-expressing lymphocyte subpopulations, including CD4+ 
cytotoxic T cells and activated B cells, including plasmablasts.   
5. Comparison of elotuzumab and placebo with regard to the impact of 
the tissue concentrations of CD4+ cytotoxic T cells and activated B 
cells subsets of interest, pre- and post-treatment submandibular 
gland biopsies.  
6. Correlation of the clonally-expanded effector subset (CD57+CD28-) 
of CD4+CTLs with disease activity. 
7. Correlation of soluble plasma SLAMF7 levels with disease activity 
and risk of relapse. 
8. SF-36 health survey.  
Accrual Objective 
Approximately 75 participants will be enrolled in the overall program, 12 
in Part 1 and 63 in Part 2. 
Study Duration 
The rate of recruitment to AIG01 is anticipated to be 0.5 participants per 
week.  
• 
The duration target for Part 1A prior to initiation of Part 1B is 21 
weeks (12 weeks of recruitment, 9 weeks of follow-up). 
• 
The duration target for Part 1B prior to initiation of Part 2 is 60 
weeks (12 weeks of recruitment, 48 weeks of follow-up). 
• 
The duration target for Part 2 is 176 weeks (128 weeks of 
recruitment, 48 weeks of follow-up). 
The total study duration is estimated to be 257 weeks (approximately 5 
years). 
Treatment Description  
Part 1   
Elotuzumab 
Participants receive either a 1-month or twelve-month regimen of 
elotuzumab, depending on enrollment phase (see Study Design Section 
3). Each intravenous dose will be 10 mg/kg, to be determined based on 
participant’s weight.  Rounding is permissible within 5% of the nominal 
dose.  The participant’s actual weight will be used for dosing.  At the 
Baseline/Day 0 visit, the participant’s screening weight will be used for 
calculation of the Baseline/Day 0 infusion dose. For all subsequent 
infusions, weight from the previous visit may be used unless weight was 


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obtained more than 42 days previously. If more than 42 days have 
elapsed since the previous visit, the participant’s current weight should 
be used for calculation.  
The 1-month regimen consists of 4 weekly doses of elotuzumab (10 
mg/kg) on days 0, 7, 14, and 21. The twelve-month regimen consists of 6 
doses at Baseline/Day 0, Week 8, Week 16, Week 24, Week 32, and 
Week 40. 
Prednisone 
Participants will receive a standardized prednisone taper, starting at 
either 40 mg orally daily or 30 mg orally daily based on doses received 
during the screening period. This will be tapered to discontinuation over 
a 10-week period. 
Part 2 
Participants receive either elotuzumab or placebo for elotuzumab in a 
2:1 ratio.  
Elotuzumab/Placebo 
It is anticipated that the twelve-month regimen from Part 1 will be used 
for the elotuzumab and placebo for elotuzumab dosing schedule, 
provided there is no safety signal detected. The pharmacist is the only 
site personnel not blinded to the treatment assignment. Placebo for 
elotuzumab will be investigational sites’ stocked 0.9% normal saline 
prepared by the site pharmacist.  
Prednisone 
Participants will receive the same standard prednisone taper as 
described in Part 1. 
Inclusion Criteria 
1. Participant must be able to understand and provide informed 
consent and be willing to comply with study procedures and follow 
up.  
2. Are at least 18 years of age and not older than 70 years of age at 
screening.    
3. Meet the ACR/EULAR Classification Criteria for IgG4-RD.  
4. Have active disease based at screening on an IgG4-RD RI ≥4, with 
disease manifestations in at least two organ systems. 
5. May have newly-diagnosed or relapsing disease at screening. 
Relapsing disease is defined as IgG4-RD that has previously been in 
remission but is now active again.   
6. May be on treatment or off treatment at the time of screening. If on 
treatment, must be willing to discontinue those other treatments 
before the baseline visit.  


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7. No history of severe allergic reactions to monoclonal antibodies.   
8. Female participants of childbearing potential must have a negative 
pregnancy test upon study entry. 
9. Female participants of childbearing potential and male participants 
with a partner of childbearing potential must agree to consistently 
and correctly use FDA approved highly effective methods of birth 
control, as shown in Appendix 8: Acceptable Contraception 
Methods for Females of Reproductive Potential, for the entire 
duration of the study and 6 months after last elotuzumab infusion. 
10. Immunization with one of the FDA authorized or licensed SARS-CoV-
2 vaccines as per CDC recommendations at the time of informed 
consent is required for study entry. Vaccination series must have 
been completed at least 2 weeks prior to start of study therapy. 
Exclusion Criteria 
1. Presence of a condition other than IgG4-RD that (e.g., asthma) is 
likely to require systemic Glucocorticoids (GC) for disease control 
during the period of the trial. 
2. Malignancy within 5 years (except successfully treated in situ cervical 
cancer, resected squamous cell or basal cell carcinoma of the skin.) 
3. The following lab values as indicators of hepatic dysfunction:  
a. Serum aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) greater than three times the upper 
limit of normal (ULN) 
b. Total bilirubin > two times the ULN unless caused by 
Gilbert’s disease. Gilbert’s disease with total bilirubin > three 
times ULN. 
c. Serum albumin < 2.5 gm/dL. 
4. Evidence of another uncontrolled condition which, in the judgment 
of the investigator, could interfere with participation in the trial 
according to the protocol. 
5. Active infection requiring hospitalization or treatment with systemic 
antimicrobial agents within the 30 days prior to treatment 
allocation/randomization. 
6. Prior use of rituximab or other B cell depleting agents within 9 
months of enrollment unless B cells have been demonstrated to 
have repopulated. 
7. Use of any investigational agent or biologic and non-biologic 
DMARDS within 5 half-lives of the agent (or 6 months if the half-life 
is unknown) prior to enrollment. 
8. Any of the following laboratory tests at the Screening Visit: 
a. White blood cell (WBC) count < 3.0 x 103/µL. 
b. Absolute neutrophil count (ANC) < 1.5 x 103/µL. 
c. Hemoglobin < 10 g/dL. 
d. Platelet count < 75 x 109/L. 


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e. Estimated glomerular filtration rate (eGFR) ≤ 45 
ml/minute/1.73m2. 
9. The use of supplemental oxygen at baseline. 
10. At or within 90 days of screening: Positive Interferon-Gamma 
Release Assay (IGRA). Indeterminate IGRAs must be repeated (with 
same or other IGRA per local policy) and shown to be negative. 
Alternatively, if the assay remains indeterminant, a participant must 
have a negative PPD. Finally, if the participant has had the Bacille 
Calmette-Guerin (BCG) vaccine or has some other condition 
complicating the interpretation of TB testing, consultation with 
infectious disease specialist must be obtained before receipt of the 
first investigational infusion.  
a. Participants diagnosed with latent TB are eligible but must 
have received appropriate prophylaxis for 30 days before 
their first investigational infusion.  
11. Medical history or serologic evidence at Screening of chronic 
infections including: 
a. Human immunodeficiency virus infection.  
b. Hepatitis B as indicated by surface antigen or hepatitis B 
core antibody positivity  
c. Hepatitis C as indicated by anti-hepatitis C antibody 
positivity; if a participant is Hepatitis C antibody positive, 
they will be eligible to participate in the study if he/she is 
negative for viral load at Screening.   
12. Live vaccines within 8 weeks of initiating study therapy.  
13. Participant is pregnant or breastfeeding, or planning a pregnancy 
while enrolled in the study. 
14. Substance use disorder, including the recurrent use of alcohol and/or 
drugs within the past year associated with clinically significant 
impairment associated with failure to meet major responsibilities at 
work, school, or home. 
15. IgG4-RD that is dominated primarily by advanced fibrotic lesions.  
Specifically, participants whose disease manifestations consist only 
of  
a. retroperitoneal fibrosis,  
b. fibrosing mediatinitis,  
c. sclerosing mesenteritis, and  
d. Riedel’s thyroiditis.   
Participants with these disease manifestations can be included, 
however, only if they have disease in 2 organ systems that is not 
of an advanced fibrotic nature and otherwise meet the Inclusion 
and Exclusion Criteria.  
16. Evidence a SARS-CoV-2 (COVID-19) infection started within the 30 
days prior to treatment allocation/randomization. Participants 


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diagnosed with SARS-CoV-2 (COVID-19) infection more than 30 days 
prior to  treatment allocation/randomization must have symptoms 
resolved and be deemed fit to participate in the trial. 
Safety Stopping Guidance 
The following events will trigger an ad hoc DSMB review (Section 
12.11.3): 
• 
Any death that is at least possibly related to elotuzumab, IgG4-
RD, or a study-mandated procedure; 
• 
Any grade 4 adverse event, including infection, that is a clinical 
event such as a sign/symptom, diagnosis, or laboratory 
abnormality with clinical consequence and at least possibly 
related to use of the investigational study medication. Any life-
threatening infusion reactions during infusion of study treatment 
or within the two-hour observation period after study treatment 
that lead to permanent discontinuation of the infusion, including 
anaphylaxis; 
• 
Two or more of the first 6 treated participants within a given 
cohort (cohorts 1a, 1b or 2) experience a drug-related adverse 
event resulting in the permanent discontinuation of study 
treatment; subsequently, if >20% of participants on study or 
within a cohort experience a drug-related adverse event 
resulting in the permanent discontinuation of study treatment; 
• 
The occurrence of a Grade 3 or higher related and unexpected 
SAE in three or more of the study participants who have received 
a study treatment; 
• 
Malignancy 
• 
Any event which in the opinion of the Protocol Chair or Medical 
Monitor merits DSMB review. 
 
Events that trigger an ad hoc DSMB review will be cumulative over Parts 
1 and 2 of the study. 


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Table of Contents 
1 
Background and Rationale ............................................................................................................................................ 19 
1.1 
Background and Scientific Rationale ..................................................................................................................... 19 
1.1.1 
IgG4-Related Disease (IgG4-RD) .................................................................................................................... 19 
1.1.2 
Current Treatment of IgG4-RD and Rationale for the Clinical Study ............................................................ 19 
1.2 
Rationale for Selection of Investigational Product or Intervention ...................................................................... 20 
1.3 
Preclinical Experience ........................................................................................................................................... 22 
1.4 
Rationale for Study Population ............................................................................................................................. 23 
1.5 
Clinical Studies ...................................................................................................................................................... 23 
1.5.1 
Rationale for Elotuzumab Dosing Schedule Change following Part 1A of Protocol AIG01 ........................... 25 
2 
Study Hypotheses/Objectives ....................................................................................................................................... 26 
2.1 
Hypotheses............................................................................................................................................................ 26 
2.2 
Mechanistic Hypotheses ....................................................................................................................................... 27 
2.3 
Primary Objectives ................................................................................................................................................ 27 
2.4 
Secondary Objectives ............................................................................................................................................ 27 
2.5 
Exploratory Objectives .......................................................................................................................................... 27 
3 
Study Design .................................................................................................................................................................. 28 
3.1 
Description of Study Design .................................................................................................................................. 28 
3.1.1 
Part 1: Open-label Phase ............................................................................................................................... 28 
3.1.2 
Transition to Part 2 ....................................................................................................................................... 30 
3.1.3 
Part 2: Randomized Phase ............................................................................................................................ 30 
3.1.4 
Study Duration .............................................................................................................................................. 31 
3.2 
Primary Endpoints ................................................................................................................................................. 32 
3.3 
Secondary Endpoints ............................................................................................................................................ 32 
3.4 
Exploratory Endpoints ........................................................................................................................................... 32 
3.5 
Description of Outcome Variables and Instruments ............................................................................................ 33 
3.5.1 
American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification 
Criteria 33 
3.5.2 
IgG4-RD Responder Index ............................................................................................................................. 33 
3.5.3 
Disease Flare Definition ................................................................................................................................ 34 
3.5.4 
Physician and Patient Global Assessment Visual Analog Scale (VAS) ........................................................... 34 
3.5.5 
Flare Guidance Document............................................................................................................................. 34 
3.5.6 
36-Item Short Form (SF-36) Health Survey ................................................................................................... 34 


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3.5.7 
ELF Score ....................................................................................................................................................... 35 
3.6 
Criteria for Evaluation ........................................................................................................................................... 35 
3.6.1 
Disease Activity ............................................................................................................................................. 35 
3.6.2 
Disease-Related Damage .............................................................................................................................. 35 
3.6.3 
Patient-Reported Outcomes ......................................................................................................................... 35 
3.6.4 
Safety ............................................................................................................................................................ 35 
3.6.5 
Serologic Indicators of Response .................................................................................................................. 35 
3.6.6 
Mechanistic Studies ...................................................................................................................................... 35 
3.7 
Stratification, Randomization, and Blinding/Masking .......................................................................................... 36 
3.7.1 
Procedure for Unblinding/Unmasking .......................................................................................................... 36 
4 
Selection of Participants ............................................................................................................................................... 37 
4.1 
Inclusion Criteria ................................................................................................................................................... 37 
4.2 
Exclusion Criteria ................................................................................................................................................... 37 
4.3 
Co-enrollment Guidelines ..................................................................................................................................... 39 
5 
Known and Potential Risks and Benefits to Participants .............................................................................................. 39 
5.1 
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert................. 39 
5.1.1 
Infusion Reactions ......................................................................................................................................... 39 
5.1.2 
Pregnancy & Lactation .................................................................................................................................. 39 
5.1.3 
Infections ....................................................................................................................................................... 40 
5.1.4 
Hepatotoxicity ............................................................................................................................................... 40 
5.1.5 
Malignancies ................................................................................................................................................. 40 
5.1.6 
Immunogenicity (Anti-Elotuzumab Antibodies)............................................................................................ 40 
5.1.7 
Other Frequently-reported Adverse Events ................................................................................................. 41 
5.2 
Risks of Other Protocol Specified Medications ..................................................................................................... 41 
5.2.1 
Corticosteroids .............................................................................................................................................. 41 
5.3 
Risks of Study Procedures ..................................................................................................................................... 41 
5.3.1 
Risks Specific to Imaging and Contrast Material ........................................................................................... 41 
5.3.2 
Risks Specific to CT Scan ................................................................................................................................ 42 
5.3.3 
Risks Specific to MRI...................................................................................................................................... 42 
5.3.4 
Risks with Peripheral Intravenous Catheters ................................................................................................ 42 
5.4 
Potential Benefits .................................................................................................................................................. 42 
6 
Investigational Regimen ................................................................................................................................................ 43 
6.1 
Elotuzumab and Placebo for Elotuzumab ............................................................................................................. 43 
6.1.1 
Product Description ...................................................................................................................................... 43 


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6.1.2 
Formulation, Packaging, and Labeling .......................................................................................................... 43 
6.1.3 
Storage Conditions ........................................................................................................................................ 43 
6.1.4 
Dosage, Preparation, and Administration ..................................................................................................... 43 
6.1.4.1 
Placebo for Elotuzumab ............................................................................................................................ 44 
6.1.4.2 
Elotuzumab Administration and Monitoring ............................................................................................ 44 
 Pre-medication .................................................................................................................................... 44 
 Administration .................................................................................................................................... 44 
 Monitoring .......................................................................................................................................... 45 
6.2 
Drug Accountability ............................................................................................................................................... 45 
6.3 
Assessment of Participant Dosing Compliance ..................................................................................................... 45 
6.4 
Toxicity Prevention and Management .................................................................................................................. 46 
6.4.1 
Infusion Reactions ......................................................................................................................................... 46 
6.4.2 
Infection ........................................................................................................................................................ 46 
6.4.2.1 
Varicella Zoster Infection and Reduced Response to Vaccination ............................................................ 47 
6.4.2.2 
General Principles for Protection fromCOVID-19 ..................................................................................... 47 
6.4.2.3 
SARS-CoV-2 Prevention ............................................................................................................................. 48 
6.4.3 
Hepatotoxicity ............................................................................................................................................... 48 
6.4.4 
Primary Malignancy ...................................................................................................................................... 48 
6.5 
Submandibular Gland Biopsy ................................................................................................................................ 49 
6.6 
Premature Discontinuation of Investigational Agent ........................................................................................... 49 
7 
Concomitant Medications ............................................................................................................................................. 50 
7.1 
Required Medications ........................................................................................................................................... 50 
7.1.1 
Prednisone .................................................................................................................................................... 50 
7.1.1.1 
Product Description .................................................................................................................................. 50 
7.1.1.2 
Formulation, Packaging, and Labeling ...................................................................................................... 50 
7.1.1.3 
Dosage and Administration ....................................................................................................................... 50 
7.2 
Standard of Care Recommended/Permitted Therapies ....................................................................................... 51 
7.3 
Prohibited Medications ......................................................................................................................................... 51 
8 
Study Procedures .......................................................................................................................................................... 52 
8.1 
Visit Windows ....................................................................................................................................................... 52 
8.2 
Unscheduled Visits ................................................................................................................................................ 52 
8.3 
Screening and Enrollment ..................................................................................................................................... 52 
8.3.1 
Evaluation of Eligibility and Randomization .................................................................................................. 52 
8.4 
General Assessments ............................................................................................................................................ 53 


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8.5 
Clinical Laboratory Assessments ........................................................................................................................... 53 
8.6 
Disease-Specific Assessments ............................................................................................................................... 53 
9 
Mechanistic Assays ....................................................................................................................................................... 54 
9.1 
Kinetics of Cell Depletion ...................................................................................................................................... 54 
9.2 
Mechanistic Assessments ..................................................................................................................................... 54 
9.3 
Effect of Elotuzumab at the Tissue Level .............................................................................................................. 54 
9.4 
Determine the Utility of Using the Clonally-expanded Effector Subset (CD57+CD28-) of CD4+CTLs as a 
Biomarker of Disease Activity ........................................................................................................................................... 55 
9.5 
Determine the Utility of Soluble Plasma SLAMF7 Levels as Indicators of Disease Activity .................................. 55 
10 Biospecimen Storage..................................................................................................................................................... 55 
11 Criteria for Participant and Study Completion and Premature Study Termination...................................................... 56 
11.1 
Participant Completion ......................................................................................................................................... 56 
11.2 
Participant Withdrawal Criteria ............................................................................................................................ 56 
11.3 
Participant Replacement ....................................................................................................................................... 56 
11.4 
Follow-up After Early Study Withdrawal .............................................................................................................. 56 
11.5 
Safety Stopping Guidance ..................................................................................................................................... 56 
12 Safety Monitoring and Reporting ................................................................................................................................. 57 
12.1 
Overview ............................................................................................................................................................... 57 
12.2 
Definitions ............................................................................................................................................................. 57 
12.2.1 
Adverse Event (AE) ........................................................................................................................................ 57 
12.2.2 
Adverse Reaction and Suspected Adverse Reaction (SAR) ........................................................................... 57 
12.2.3 
Unexpected Adverse Event/Reaction ........................................................................................................... 57 
12.2.4 
Serious Adverse Event (SAE) ......................................................................................................................... 58 
12.3 
Grading and Attribution of Adverse Events .......................................................................................................... 58 
12.3.1 
Grading Criteria ............................................................................................................................................. 58 
12.3.2 
Attribution Definitions .................................................................................................................................. 59 
12.4 
Collecting and Recording of Adverse Events......................................................................................................... 60 
12.4.1 
Collection Period ........................................................................................................................................... 60 
12.4.2 
Collecting Adverse Events ............................................................................................................................. 60 
12.4.3 
Recording Adverse Events ............................................................................................................................. 60 
12.5 
Reporting Adverse Events and Serious Adverse Events to Sponsor: DAIT/NIAID ................................................. 60 
12.5.1 
Reporting Adverse Events ............................................................................................................................. 60 
12.5.2 
Reporting of Serious Adverse Events ............................................................................................................ 61 
12.6 
Reporting to Health Authorities ............................................................................................................................ 62 


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12.6.1 
Annual Reporting .......................................................................................................................................... 62 
12.6.2 
Expedited Safety Reporting ........................................................................................................................... 62 
12.7 
Reporting of Adverse Events to IRBs/IECs ............................................................................................................ 62 
12.8 
Reporting Pregnancy ............................................................................................................................................. 62 
12.9 
Reporting Unanticipated Problems ....................................................................................................................... 63 
12.10 Review of Safety Information ............................................................................................................................... 63 
12.10.1 Medical Monitor Review ............................................................................................................................... 63 
12.11 Data Safety and Monitoring Board Review ........................................................................................................... 63 
12.11.1 Routine DSMB Reviews ................................................................................................................................. 63 
12.11.2 Protocol-Defined Interim Safety Reviews ..................................................................................................... 64 
12.11.3 Ad hoc DSMB Reviews .................................................................................................................................. 64 
13 Statistical Considerations and Analytical Plan .............................................................................................................. 64 
13.1 
Overview ............................................................................................................................................................... 64 
13.2 
Endpoints .............................................................................................................................................................. 65 
13.3 
Measures to Minimize Bias ................................................................................................................................... 65 
13.4 
Analysis Plan .......................................................................................................................................................... 65 
13.4.1 
Analysis Populations ..................................................................................................................................... 65 
13.4.2 
Primary Analysis of Primary Endpoint ........................................................................................................... 65 
13.4.3 
Supportive Analyses of the Primary Endpoint .............................................................................................. 66 
13.4.4 
Analyses of Secondary and Other Endpoints ................................................................................................ 66 
13.4.5 
Descriptive Analyses ..................................................................................................................................... 67 
13.5 
Interim Analyses .................................................................................................................................................... 67 
13.5.1 
Interim Analysis of Efficacy Data ................................................................................................................... 67 
13.5.2 
Interim Analysis of Safety Data ..................................................................................................................... 67 
13.5.3 
Futility Analysis ............................................................................................................................................. 68 
13.6 
Statistical Hypotheses ........................................................................................................................................... 68 
13.7 
Sample Size Considerations .................................................................................................................................. 69 
14 Identification and Access to Source Data ..................................................................................................................... 70 
14.1 
Source Data ........................................................................................................................................................... 70 
14.2 
Access to Source Data ........................................................................................................................................... 70 
15 Quality Assurance and Quality Control ......................................................................................................................... 70 
16 Protocol Deviations ....................................................................................................................................................... 71 
16.1 
Protocol Deviation Definitions .............................................................................................................................. 71 
16.2 
Reporting and Managing Protocol Deviations ...................................................................................................... 71 


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17 Ethical Considerations and Compliance with Good Clinical Practice ............................................................................ 71 
17.1 
Statement of Compliance ..................................................................................................................................... 71 
17.2 
Informed Consent Process .................................................................................................................................... 72 
17.3 
Privacy and Confidentiality ................................................................................................................................... 72 
18 Publication Policy .......................................................................................................................................................... 72 
19 References .................................................................................................................................................................... 73 
20 Appendices .................................................................................................................................................................... 75 
20.1 
Appendix 1: Schedule of Visits and Assessments ................................................................................................. 75 
20.2 
Appendix 2: ACR/EULAR........................................................................................................................................ 80 
20.2.1 
Immunostaining for ACR/EULAR Classification ............................................................................................. 83 
20.3 
Appendix 3: IgG4-RD RI ......................................................................................................................................... 84 
20.4 
Appendix 4: PhGA and PGA VAS ........................................................................................................................... 86 
20.5 
Appendix 5: Flare Documentation Guide .............................................................................................................. 88 
20.6 
Appendix 6: SF-36 Health Survey ........................................................................................................................ 120 
20.7 
Appendix 7: Clinical Criteria for Diagnosing Anaphylaxis ................................................................................... 126 
20.8 
Appendix 8: Acceptable Contraception Methods for Females of Reproductive Potential ................................. 127 
 
 
 


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Glossary of Abbreviations 
ACE 
Autoimmunity Centers of Excellence 
ACR/EULAR 
American College of Rheumatology/European League Against Rheumatism 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BCG 
Bacille Calmette-Guerin 
BMS 
Bristol-Myers Squibb Co. 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
CRP 
C-Reactive protein  
CTL 
Cytotoxic T lymphocytes 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
ELF 
Enhanced Liver Fibrosis 
ESR 
Erythrocyte sedimentation rate 
EUA 
Emergency Use Authorization 
FACS 
Fluorescence-activated cell sorting 
FDA 
Food and Drug Administration 
HA 
Hyaluronic acid 
HCG 
Human chorionic gonadotropin 
ICH 
International Conference on Harmonisation 
IgG4-RD 
IgG4-related disease 
IgG4-RD RI 
IgG4-RD Responder Index 
IGRA 
Interferon gamma release assay  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
mAb 
Monoclonal antibody 
MCAR 
Missing-completely-at-random 
MGH 
Massachusetts General Hospital 
MIT 
Massachusetts Institute of Technology  
mITT 
Modified intent-to-treat 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institute of Health 
NK 
Natural killer 
PBMC 
Peripheral blood mononuclear cells 
PGA 
Patient Global Assessment 
PhGA 
Physician Global Assessment  
PI 
(Site) Principal investigator 
PIIINP 
Propeptide of type III procollagen  
PMA 
Phorbol myristate acetate 


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PP 
Per protocol 
RT-PCR 
Reverse transcription polymerase chain reaction 
SCCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SF-36 
36-Item Short Form Health Survey 
SLAMF7 
Signaling lymphocyte activation molecule family 7 
SRC 
Safety Review Committee 
SUSAR 
Serious unexpected suspected adverse reaction 
TCR/BCR 
T cell receptor/B cell receptor 
TFH 
T follicular helper 
TIMP-1 
Tissue inhibitor of metalloproteinases 1  
TPH 
Peripheral helper T 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WBC 
White blood cell 
 
 
 


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1 Background and Rationale  
1.1 Background and Scientific Rationale 
1.1.1 
IgG4-Related Disease (IgG4-RD) 
IgG4-RD is a chronic fibro-inflammatory condition that can affect virtually every organ system, including the 
pancreas, biliary tract, salivary and lacrimal glands, orbits, lungs, kidneys, meninges, pituitary gland, prostate and 
thyroid. It may also involve the retroperitoneum. This multi-organ immune-mediated condition, once regarded as a 
group of isolated, single-organ diseases, is now recognized to be an overarching, single-disease entity linked by 
common histopathological and immunohistochemical features. The histopathological features include a dense 
lymphoplasmacytic infiltrate consisting of T cells and IgG4+ plasma cells, storiform fibrosis and obliterative phlebitis. 
Immunostaining of affected tissues generally demonstrates a ratio of ≥40% IgG4/IgG+ plasma cells [1]. Serum IgG4 
concentrations are elevated in at least 50-60% of cases before the initiation of treatment [2].  
 
IgG4-RD tends to afflict middle-aged to elderly individuals. Although IgG4-RD can affect a single organ at 
presentation, it is not uncommon for participants to present with or develop multi-organ disease. As the disease 
progresses, additional organs develop lesions and the cellular inflammation characterizing early disease moves 
toward a more fibrotic stage, causing major tissue damage, dysfunction and ultimately organ failure. 
It is unclear whether IgG4 itself is involved in the pathogenesis of the disease.  T cells comprise the major 
inflammatory cell in this disease. In fact, two CD4+ T cells are believed to play crucial roles in this condition:  
• 
A CD4+ cytotoxic T lymphocyte (CTL) bearing signaling lymphocyte activation molecule family 7 (SLAMF7) on 
its surface, secreting profibrotic cytokines IL-1B and transforming growth factor-B1 (TGF-B1) and interferon-
gamma (IFN-gamma), as well as cytotoxic molecules such as perforin and granzyme B.  
• 
A CD4+ T follicular helper (TFH) cell, known to drive the class switch within lymph nodes and extra-nodal 
germinal centers [3]  
In addition, several B cell subsets have recently been described by flow cytometry to be elevated in the peripheral 
blood of IgG4-RD participants. Circulating IgG4+ plasmablasts (CD19lowCD38+CD20-CD27+) are elevated in active 
disease as compared to individuals with other diseases and normal controls, even in IgG4-RD participants with 
normal IgG4 serum levels. Total plasmablasts can therefore be utilized as a diagnostic feature of IgG4-RD [4, 5]. 
1.1.2 
Current Treatment of IgG4-RD and Rationale for the Clinical Study 
The goals of IgG4-RD treatment are to reduce inflammation and organ swelling and to prevent or reverse tissue 
fibrosis. Aggressive treatment is warranted to prevent organ failure when vital organs are involved. For example, 
cholangitis due to IgG4-RD can lead to hepatic failure; IgG4-related (type 2) autoimmune pancreatitis can lead to 
failure of the endocrine pancreas, exocrine pancreas, or both; and IgG4-related tubulointerstitial nephritis can lead to 
renal failure.  
 
At the present time, glucocorticoids at daily doses of 0.6 mg/kg daily for 2 to 4 weeks followed by tapering to low 
doses (or discontinuing altogether) over a total of 2-4 months is the first line of therapy. Although this approach is 
effective initially in most participants, the relapse rate upon tapering or discontinuation is high [6]. In addition, the 
long-term use of glucocorticoids in older populations such as that affected by IgG4-RD can lead to many untoward 
side effects such as weight gain, diabetes, osteoporosis, bone fracture, hypertension, and infection.   
 


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In an open-label trial from Japan in which 60 participants were treated with prednisone alone for one year, the 
protocol called for participants to continue on maintenance prednisone between 5 mg/day and 10 mg/day after 
achieving disease stability.  Despite the continuation of prednisone in all participants at doses closer to 10 mg/day 
than 5 mg/day, only 66% of the participants treated according to this protocol achieved and maintained disease 
remission at one year [7].  Another trial from China compared participants treated with prednisone alone (tapered to 
between 5 mg/day and 10 mg/day) to the combination of cyclophosphamide and prednisone [8].  Despite the fact 
that participants in the prednisone only arm continued their prednisone throughout the observation period, disease 
relapses occurred in 39% of the participants. Twelve percent of the participants in the cyclophosphamide/prednisone 
arm failed, but the known toxicities of this combination of therapies are unappealing for broad clinical use. These 
trials underscore the shortcomings of glucocorticoids as monotherapy for IgG4-RD and emphasize the importance of 
identifying new treatment approaches.      
 
Immunosuppressive medications such as azathioprine, mycophenolate mofetil, and methotrexate have been used as 
glucocorticoid-sparing agents, with no clear evidence of efficacy [6, 9, 10]. A high disease response rate has been 
observed in one 30-participant open-label trial with rituximab, utilizing the IgG4-RD Responder Index (IgG4-RD RI) as 
a measure of disease response [11]. A single case report from Japan described efficacy of abatacept in a participant 
with multi-organ IgG4-RD whose symptoms and signs of disease were refractory to B cell depletion with rituximab 
[12].   
1.2 Rationale for Selection of Investigational Product or Intervention 
Elotuzumab (Bristol-Myers Squibb) is a humanized, IgG1 monoclonal antibody (mAb) targeted against SLAMF7, a 
glycoprotein expressed on myeloma cells as well as on cells of the normal B lymphocyte lineage, natural killer (NK) cells, 
and a number of CD4+ and CD8+ T cell subsets. SLAMF7 has been not been detected on either hematopoietic stem cells 
or on other normal tissues. SLAMF7 is highly expressed on myeloma cells independent of cytogenetic abnormalities. It is 
also expressed on the CD4+ CTL that we believe to be the crucial driver of the fibroinflammatory processes central to 
IgG4-RD, and on cells of the B lymphocyte lineage that also play crucial roles in IgG4-RD [3-5, 13].             
In participants with myeloma, elotuzumab is known to interact directly with NK cells. This enhances the anti-myeloma 
activity of these cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma 
cells and facilitates the interaction with NK cells to mediate the killing of myeloma cells through antibody-dependent 
cellular cytotoxicity (ADCC). The presence of SLAMF7 on two types of cells considered crucial to the pathophysiology of 
IgG4-RD, namely cells of the B lymphocyte lineage and CD4+CTLs, suggest that this therapy may be highly effective in 
IgG4-RD [3-5, 14-16].   
An overview of the pathophysiology of IgG4-RD is shown in Figure 1 below [17].  The cellular interaction believed critical 
to the disease is that involving cells of the B lymphocyte lineage and a CD4+CTL, both of which express SLAMF7 on their 
surface:  


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Figure 1. Overview of the Pathophysiology of IgG4-RD 
 
Figure 1 Legend. The central pathophysiologic event in IgG4-RD is believed to be the presentation of antigen by cells of the B-lymphocyte lineage 
(plasmablasts and some double negative [CD19+IgD-CD27-] B cells) to CD4+ cytotoxic T lymphocytes. Both these CD4+CTLs and the antigen-
presenting cells are SLAMF7-positive, making SLAMF7 an appealing therapeutic target. The class switch to IgG4 production by cells of the B lineage 
appears to be driven by T follicular helper cells (TFH cells) via the secretion of IL-4 and IL-10. The role of serum IgG4 in IgG4-RD may be a counter-
regulatory one but in some cases of extremely high serum IgG4 concentrations immune complexes appear to contribute to tissue injury [17]. 
 
The CD4+ CTLs in IgG4-RD secrete several pro-fibrotic cytokines, including IL-1beta and transforming growth factor-beta 
[3]. Moreover, they are also capable of perforin- and granzyme B-mediated cytolysis. We have demonstrated that: 1) 
these CD4+CTLs accumulate within tissue lesions; 2) that they represent the dominant T cell population in these affected 
tissues; and that they actively produce these mediators in situ [3].  
Our group has also demonstrated that participants with IgG4-RD have elevations in circulating plasmablasts [4, 5]. 
Because B-cell depleting therapy with anti-CD20 monoclonal antibody rituximab leads to both profound clinical 
responses and to declines in CD4+CTLs [11, 18, 19], we suspect that activated B cells within affected tissues drive the 
activation of cytotoxic CD4+T cells at sites of disease. Elotuzumab will also eliminate B lymphocyte lineage cells, which 
bear SLAMF7 on their surface and provide essential support to the CD4+SLAMF7+CTL [4, 5, 15, 16]. Thus, this trial will 


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address a fundamental and important question in IgG4-RD: do CD4+SLAMF7+CTLs and their interaction with SLAMF7+ B 
cells truly drive the critical fibroinflammatory mechanisms of IgG4-RD? 
1.3 Preclinical Experience 
Elotuzumab is approved for use in multiple myeloma but has not been used before in participants with IgG4-RD or in 
participants with other autoimmune disease.  An in vitro study using T lymphocytes from a participant with IgG4-RD was 
performed to gain insight into the potential effect of elotuzumab on IgG4-RD.  This experiment, performed in the 
laboratory of Dr. Shiv Pillai at the Ragon Institute in Cambridge, MA, is described below.  
The objective was to understand the in vitro effects of elotuzumab on CD4+CTLs (and the small subset of TFH cells 
expressing SLAMF7 in terms of cell death and activation).   
A co-culture experiment using peripheral blood mononuclear cells (PBMCs) from an IgG4-RD participant with a large 
expansion of CD4+CTLs was performed. Cells were thawed and incubated overnight in medium. PBMCs alone were used 
as a negative control. Varying doses of elotuzumab (0.0001, 0.01 and 1.0 ug/mL) were compared to positive controls 
(phorbol myristate acetate (PMA)/ionomycin & CD3/CD28 for T cell activation, staurosporine for apoptosis). Cells were 
incubated for 4 hours and then stained for flow cytometry. Annexin and 7-AAD were used to quantify apoptosis and cell 
death. CD69 and CD40L were used as surface markers of T cell activation.  
Figure 2A below illustrates marked cell death induced by elotuzumab in a dose-dependent manner.  Cell death only 
occurred in the SLAMF7-expressing T cell populations, and it occurred quickly (this was a 4-hour assay). This suggests 
that elotuzumab induces cell death by its specific affinity to SLAMF7. To ensure the administration of elotuzumab would 
not result in activation of autoreactive T cells in IgG4-RD participants, we also measured surface expression of T cell 
activation markers following this co-culture experiment.  
Figure 2B below demonstrates the dose-dependent decline in CD69 expression as a percentage of the total CD4+CTLs 
following elotuzumab exposure. Positive controls using CD3/CD28 Dynabeads and PMA/ionomycin were used to 
demonstrate the capacity of the cells to express activation markers with a 4-hour incubation. Taken together, these data 
support the idea that elotuzumab does not activate CD4+CTLs. On the contrary, elotuzumab induces profound cell death 
of the SLAMF7-expressing CD4 CTLs as well the as SLAMF7-expressing TFH cells. 
 
Figure 2A. Dose-dependent cell death induced by elotuzumab only affecting SLAMF7-expressing CD4+ T cells (CD4+CTLs, red; SLAMF7+TFH cells, 
purple; SLAMF7-CD4+ T cells in blue).  
Figure 2A. Dose vs Response                                   Figure 2B. CD4+CTL Activation vs Elotuzumab Dose   


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Figure 2B. CD4+CTLs were not activated by elotuzumab exposure but rather the percent activation was reduced as demonstrated by the red 
columns compared to PBMCs alone (black column). Two different positive controls were used (CD3/CD28 and PMA/ionomycin) to ensure CD4+CTLs 
were capable of activation in this 4-hour assay. 
1.4 Rationale for Study Population 
IgG4-RD is a recently-described disease for which no approved therapy exists. IgG4-RD causes important end-organ 
damage, including failure of both the exocrine and endocrine pancreas (autoimmune pancreatitis); hepatic failure 
(cholangitis); kidney failure from intrinsic renal disease (tubulointerstitial nephritis); obstructive nephropathy and 
chronic pain (retroperitoneal fibrosis); dysfunction of other organs (orbits, lung); and death from a variety of causes 
(complications of aortitis, pulmonary disease, meningeal involvement, other).  Prednisone is an effective therapy in 
many participants but does not cure the disease.  Moreover, the use of glucocorticoids in a disease that affects a middle-
aged to elderly population and has a predilection for causing endocrine pancreatic failure (i.e., diabetes) is problematic. 
The SLAMF7 molecule, expressed on both multiple B cell subsets and a crucial CD4+CTL, offers a promising targeted 
approach to the treatment of IgG4-RD.  The administration of elotuzumab should eliminate the cell types that are 
central to the critical cellular interaction that drives the pathophysiology of IgG4-RD, offering a potentially 
glucocorticoid-free approach to remission induction.  We have therefore designed a two-part trial, which will first (Part 
1) gather data about the safety of this treatment approach in this participant population and then (Part 2) help 
understand the efficacy of this intervention.  
This study plans to enroll adult participants who meet the American College of Rheumatology/European League Against 
Rheumatism (ACR/EULAR) Classification Criteria for IgG4-RD, and who have active IgG4-RD with disease manifestations 
in at least two organ systems. The study will not restrict enrollment to the subset of patients with elevated serum IgG4 
level; however, patients with normal serum IgG4 concentrations typically have disease limited to a single organ or body 
area, and we therefore anticipate enrichment in the percentage of patients with elevated serum IgG4 concentrations 
greater than the 50-60% of cases reported in previous cohort studies [2].  A planned subgroup analysis will evaluate the 
efficacy of elotuzumab in participants with elevated serum IgG4 level that is detected in the 6 months prior to initiation 
of study therapy.  
The total duration of follow-up in this trial will be 48 weeks. The purpose of this extended follow-up is to provide data on 
the duration of effect of elotuzumab that are comparable to those available for prednisone[7], cyclophosphamide [8], 
and rituximab[11], as other therapies employed for the treatment of IgG4-RD. In a 30-patient open-label trial of 
rituximab, for example, 40% of the patients treated with rituximab remained in sustained remission 12 months after 
induction therapy. 
1.5 Clinical Studies  
Elotuzumab, a humanized, IgG1 monoclonal antibody, targets SLAMF7 and is approved for use in refractory multiple 
myeloma. The drug is the first therapy ever awarded a breakthrough designation for any indication by the U.S. Food & 
Drug Administration (FDA).  Elotuzumab has been a well-tolerated therapy in multiple myeloma [20-23]. Myeloma 
participants are typically elderly, frequently have substantial co-morbidities, and generally undergo intensive treatment 
regimens consisting not only of elotuzumab but also high-dose glucocorticoids and chemotherapeutic agents.  The chief 
concern stems from the potential for infusion reactions, which are reported in only 10% of myeloma participants and are 
nearly always only grade 1 or 2 (1% of reactions are grade 3) [21]. 
Elotuzumab has been administered to participants with multiple myeloma in 16 clinical studies that are either 
completed (fully or for the primary endpoint) or ongoing. Elotuzumab has been combined with other agents in most of 
these studies, aside from dose-ranging studies of elotuzumab alone.  These studies include: 


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• 
Elotuzumab plus thalidomide and dexamethasone  
• 
Elotuzumab plus lenalidomide and dexamethasone  
• 
Elotuzumab plus pomalidomide and dexamethasone 
• 
Elotuzumab plus pomalidomide, nivolumab, and dexamethasone 
• 
Elotuzumab plus bortezomib and dexamethasone 
For the purpose of treating multiple myeloma, elotuzumab is used invariably in combination with one of these or other 
therapies.  
The elotuzumab dose that we will use in IgG4-RD is 10 mg/kg, administered in two regimens, one regimen that is one 
month long (four administrations) and the other that is twelve months long (six administrations).  The dose of 10 mg/kg 
is the FDA approved dose for refractory multiple myeloma, a malignancy of plasma cells. Patients with multiple myeloma 
begin their treatment by receiving one elotuzumab infusion weekly for eight doses and then transition to receiving the 
medication every two weeks on an ongoing basis until disease progression or unacceptable toxicity. The rationale for the 
continued infusions in multiple myeloma is to maintain a steady state of plasma cell depletion.   Although we will 
employ the same FDA-approved dose in our IgG4-RD population, the regimens we will employ have significantly fewer 
doses than those used in multiple myeloma because we anticipate a more prolonged treatment response in IgG4-RD, a 
non-malignant condition.  We believe that these regimens will heighten the safety of elotuzumab in this IgG4-RD 
participant population compared to the myeloma populations in which it has been tested previously.  For the purposes 
of assessing safety, we discuss below the outcomes of two trials in multiple myeloma using elotuzumab monotherapy.  
These were known as CA204011 and HuLuc63-1701. Both of the trials discussed below were small, early phase studies.  
A more complete discussion of risks as described in the package insert and Investigator’s Brochure for elotuzumab are 
discussed in Section 5.1. 
CA204011 (NCT01441973) 
This study was entitled: “A Phase 2 Biomarker Study of Elotuzumab (Humanized anti-SC1 Monoclonal IgG1 Antibody) 
Monotherapy to Assess the Association Between NK Cell Status and Efficacy in High Risk Smoldering Myeloma”.  The trial 
enrolled 31 participants.  Participants received elotuzumab 20 mg/kg intravenous (IV) on Days 1 and 8 of Cycle 1 and Day 
1 of Cycle 2 and beyond in Arm 1 and elotuzumab 10 mg/kg weekly for 4 weeks in Cycles 1 and 2 and every other week 
in Cycles 3 and above in Arm 2.  
No deaths occurred on treatment or within 60 days after end of treatment. Two participants died more than one year 
after receiving the study drug: specifically, at 685 days (22.5 months) and at 1183 days (38.9 months) after the last dose. 
Serious adverse events (SAEs) were reported in a total of 15 participants: 8 (53.3%) participants in the 20-mg/kg dose 
arm and 7 (43.8%) of those in the 10-mg/kg dose arm. SAEs deemed related to study drug occurred in 1 (6.7%) 
participant in the 20-mg/kg dose arm (Grade 2 infusion-related reactions) and in 2 (12.5%) participants in the 10-mg/kg 
dose arm (Grade 3 pneumonia and Grade 4 dyspnea). The pneumonia and dyspnea events were the only Grade 3 to 4 
study drug-related SAEs.  
Adverse events (AEs) leading to discontinuation from study drug regardless of causality occurred in a total of 6 
participants, of whom 5 participants had Grade 3 to 4 AEs. No AE that led to discontinuation was considered related to 
study drug.  
All infusion reactions were Grade 1 to 2 in intensity, and at least 1 infusion reaction occurred in 4 (26.7%) participants in 
the 20-mg/kg dose arm and 1 (6.3%) participant in the 10-mg/kg dose arm. No participant discontinued study drug due 
to an infusion reaction.  


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Second primary malignancies were reported in 1 (6.7%) participant in the 20-mg/kg dose arm and in 3 (18.8%) 
participants in the 10-mg/kg dose arm. The second primary malignancy occurring in the 20-mg/kg dose arm was a 
squamous cell carcinoma that occurred >1.5 years after last dose of study drug. The study-drug-unrelated Grade 3 
malignancy AEs in the 10-mg/kg dose arm renal cell carcinoma, prostate cancer, and endometrial cancer.     
Few or no Grade 3 to 4 hematology, chemistry, liver, or renal laboratory test results were reported. No instances of 
possible drug-induced liver injury occurred.  
HuLuc63-1701 (NCT00425347)  
This trial was entitled: “Phase 1, Multi-Center, Open-label, Dose Escalation Study of Elotuzumab (Humanized anti-CS1 
Monoclonal IgG1 antibody) in Participants with Advanced Multiple Myeloma”. The trial enrolled 35 participants.  Four 
doses of elotuzumab IV infusion given every other week in 1 of the following dose arms: 0.5, 1, 2.5, 5, 10, and 20 mg/kg. 
In Study HuLuc63-1701, the safety profile was favorable at all doses. In the 2.5-mg/kg dose arm, 1 out of the first 3 
participants dosed experienced a dose-limited toxicity, a grade 3 serum creatinine elevation.  Subsequently, the dose 
arm was expanded to include another 3 participants. No further dose-limiting toxicities occurred in the 2.5-mg/kg dose 
arm, and dosing continued up to the 20-mg/kg dose arm. In the 20-mg/kg dose arm, 1 participant experienced a dose-
limiting toxicity, a grade 3 hypersensitivity following the first elotuzumab infusion. Thus, no maximum tolerated dose of 
elotuzumab has been identified. Doses as high as 20 mg/kg have been tolerated in participants with multiple myeloma. 
This is two times higher than the FDA-approved dose (10 mg/kg), which is the dose we will employ in this IgG4-RD trial.  
The most common AEs reported in HuLuc63-1701 were chills (38.2%), fatigue (38.2%), pyrexia (38.2%), cough (29.4%), 
headache (29.4%), and anemia (26.5%). There was no dose-dependent pattern observed with respect to the type or 
frequency of SAEs.  AEs that led to discontinuation included Grade 3 migraine and Grade 4 congestive cardiac failure (1 
participant in the 0.5 mg/kg group) and Grade 3 hypersensitivity (1 participant in the 20 mg/kg group).  
The primary causes of death were disease progression (1 participant each in the 0.5, 5, and 20 mg/kg groups) and renal 
failure (1 participant in the 5 mg/kg group).  
1.5.1 
Rationale for Elotuzumab Dosing Schedule Change following Part 1A of Protocol AIG01 
Prior to this study, elotuzumab had not been administered to patients beyond oncology indications. Evidence about 
the duration of elotuzumab’s effect in IgG4-RD, therefore, need to be derived from Parts 1A and 1B. Experience with 
elotuzumab in the six patients enrolled Part 1A led to important protocol modifications. The intent of these 
modifications is to optimize the potential for treatment efficacy in remission maintenance over 48 weeks. The 
modifications designed to enhance efficacy are discussed below. The goal is to establish safety and gain insight into 
potential treatment efficacy into Part 1B, and then to test this hypothesis definitively in Part 2, a randomized, double-
blind, placebo-controlled trial.   
Experience in Part 1A suggests that in IgG4-RD, as in multiple myeloma, elotuzumab needs to be re-administered at 
some interval. A common pattern was observed in the first six patients enrolled and treated with four weekly 
elotuzumab infusions. Approximately 1-3 months following the fourth elotuzumab infusion, the start of elevations in 
serum IgG4 concentrations was observed. This implies the possibility of recurrent immunologic activity. Clinical 
experience outside AIG01 suggests that immunological activity is likely to be followed by the resumption of clinical 
activity, usually over a period of a few months [2, 17]. 


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Four patients treated with the Part 1A regimen remain without clinical signs of disease activity: two have completed 
48 weeks of follow-up with no clinical signs of disease, and the other two continue in follow-up at this time with no 
clinical signs of active disease. Each  of these patients, however, had evidence of recurrent immunological activity as 
evidenced by rises in serum IgG4 concentrations between 1 and 3 months after their final elotuzumab infusion. In 
addition, one patient had an excellent response to remission induction, but had a mild clinical relapse characterized 
by a recurrent cough at 23 weeks; one patient, who had multi-organ disease at baseline and the highest serum IgG4 
concentration of any patient, had a clinical relapse at 10 weeks. 
The serological findings related to IgG4 concentrations are supported by flow cytometry investigations. Serial flow 
cytometry studies on all six patients demonstrate swift, nearly complete depletions of the cell types of interest: 
namely, the CD4+ and CD8+ cytotoxic T lymphocytes, plasmablasts, and DN3 B cells. Steep declines of each cell type 
were observed quickly following receipt of elotuzumab, often by 48 hours following the first infusion. These cells 
begin to re-constitute at varying intervals, averaging approximately 6 weeks across the 6 patients and occurring 
earlier for the patient with early clinical relapse. 
The transient depleting effect of elotuzumab observed in IgG4-RD is consistent with the therapeutic strategy 
developed for multiple myeloma. Our observations in Part 1A suggest that re-treatment of patients with elotuzumab 
at some regular interval will be required. This fits the pattern of treatment with other monoclonal antibodies for 
other autoimmune diseases, most of which require re-treatment on some regular basis. As examples, re-treatment 
with infliximab every six weeks is a standard treatment approach for Crohn’s disease, rheumatoid arthritis, and 
ankylosing spondylitis. 
Because clinical manifestations of active IgG4-RD generally trail serological elevations in IgG4 concentrations, 
modifications to Parts 1B and 2 of the protocol will include the infusion of elotuzumab every eight weeks starting at 
Baseline/Day 0, and followed by infusions at Weeks 8, 16, 24, 32, and 40. This elotuzumab + 10-week prednisone 
taper appears likely to establish disease control in a substantial majority of patients treated in this fashion. Regularly 
planned re-treatment of patients in Part 1B will permit important insights into the potential efficacy of every 8-week 
elotuzumab infusions for the maintenance of remission.    
Finally, the observations from Part 1A also underscore the importance of blinding both the investigators and 
participants to serum IgG4 concentrations in the randomized, double-blind part of the elotuzumab in IgG4-RD trial 
program.  
2 Study Hypotheses/Objectives 
2.1 Hypotheses 
1. Elotuzumab is safe in IgG4-RD.  To provide initial confirmation that targeting SLAMF7 is a safe therapeutic 
strategy in IgG4-RD, we will enroll 12 participants in Part 1 of this proposal to receive elotuzumab in one of two 
regimens differing in both intensity and duration, with protocolized monitoring for treatment-related adverse 
effects.   
2. A twelve month course (six administrations) of elotuzumab will induce reduction in disease activity in IgG4-RD. 
This hypothesis will be tested in Part 2 of this proposal, a randomized, double-blind, placebo-controlled trial. The 
IgG4-RD RI will be used to quantify disease activity [24].  
3. Because elotuzumab will eliminate effector cells with pro-fibrotic function, elotuzumab-induced remission will 
correlate with declining Enhanced Liver Fibrosis (ELF) scores.  The ELF score is an indirect measure of fibroblast 
activation and extracellular matrix deposition [14, 25, 26].  


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2.2 Mechanistic Hypotheses 
1. CD4+CTLs will decline at a slower rate compared to activated B cells. This is because cytotoxic T lymphocytes are 
evolutionarily resistant to cytotoxicity, as evidenced by their capacity for serial killing and ability to endocytose 
cytotoxic granules [27, 28]. We also acknowledge an alternative hypothesis: namely that activated B cells will 
decline at a slower rate compared to CTLs. This is because SLAMF7 engagement on activated B cells results in B 
cell growth and survival [29].   
2. Elotuzumab achieves tissue-level depletion of SLAMF7-expressing lymphocyte sub-populations.  
3. Expansion of the effector (CD57+CD28-) CD4+CTL subset and oligoclonality correlate with disease activity and 
decline in a manner concordant with elotuzumab-induced clinical improvement.  
4. Elotuzumab failure will be predicted by the failure to eliminate (CD57+CD28-) CD4+CTLs as determined by 
peripheral blood flow cytometry.  
5. Soluble SLAMF7 levels correlate with disease activity.    
2.3 Primary Objectives 
Part 1: To determine the safety and tolerability of the addition of elotuzumab to prednisone in participants with 
IgG4-RD. 
Part 2: To compare the effect of the addition of elotuzumab versus placebo to prednisone on the IgG4-RD RI at 48 
weeks in participants with IgG4-RD. 
2.4 Secondary Objectives 
1. To compare the effect of the addition of elotuzumab versus placebo to prednisone on complete remission at 48 
weeks. 
2. To compare the effect of the addition of elotuzumab versus placebo to prednisone on the number of disease 
flares (as defined in Section 3.5.3) per participant over time.   
3. To compare the effect of the addition of elotuzumab versus placebo to prednisone on the change from baseline 
in Physician Global Assessment (PhGA) at 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 weeks. 
4. To compare the effect of the addition of elotuzumab versus placebo to prednisone on Patient Global 
Assessment (PGA) at 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 weeks. 
5. To compare the effect of the addition of elotuzumab versus placebo to prednisone on safety.  
2.5 Exploratory Objectives 
1. To compare the effect of the addition of elotuzumab versus placebo to prednisone on serum immunoglobulin 
levels, IgG subclass concentrations, IgE levels, eosinophils, and serum C3 and C4 levels.  
2. To compare the effect of the addition of elotuzumab versus placebo to prednisone on participants’ ELF scores.  
3. To evaluate the effect of elotuzumab on CD4+ T cells and B cell subsets, specifically:  
a. CD4+ cytotoxic T lymphocytes 
b. CD8+ cytotoxic T lymphocytes 
c. CD4+ T follicular helper cells 
d. CD4+ peripheral helper T cells 
e. Plasmablasts 
f. Activated B cells, including double-negative (CD19+IgD-CD27-) B cells 
4. To determine the kinetics of cell depletion induced by elotuzumab on disease-associated, SLAMF7-expressing 
lymphocyte subpopulations including CD4+ cytotoxic T cells and activated B cells, including plasmablasts.   
5. To determine the effect of elotuzumab at the tissue level, using submandibular gland biopsies in participants 
with submandibular gland disease who consent separately to biopsies before and after treatment. 


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6. To determine the utility of using the clonally-expanded effector subset (CD57+CD28-) of CD4+CTLs as a 
biomarker of disease activity. 
7. To determine the utility of soluble plasma SLAMF7 levels as indicators of disease activity and predictors of 
disease relapse.   
8. To evaluate the longitudinal profile of patient reported outcomes on quality of life over the study period using 
the SF-36 health survey. 
3 Study Design 
3.1 Description of Study Design  
This is a two-part multi-center clinical trial in participants with active IgG4-RD.  Part 1 is an open-label, dose escalation 
phase to determine the safety of elotuzumab for investigation in IgG4-RD. If the addition of elotuzumab to prednisone is 
determined to be safe, Part 2 will be initiated as a randomized, placebo-controlled, double-blinded trial. Part 2 will 
compare the effects of the addition of elotuzumab versus placebo to prednisone in participants with IgG4-RD. 
Approximately 75 participants with active IgG4-RD will be enrolled in the overall program, 12 in Part 1 and 63 in Part 2. 
Figure 3. Overall Study Design Schema 
 
 
 
3.1.1 
Part 1: Open-label Phase  
In Part 1, approximately 12 participants will be enrolled into one of two elotuzumab treatment regimens. The first six 
participants will receive 1 month of treatment (Cohort 1a). One month after the last participant in Cohort 1a has 
completed the one-month regimen and the week 9 visit has occurred, a Safety Review Committee (SRC) review will 


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be performed to determine the safety of moving to Cohort 1b, where six participants will receive  the twelve-month 
regimen. Elotuzumab will be administered as follows:  
Cohort 1a: One-month regimen: four weekly doses at 10 mg/kg on Days 0, 7, 14, 21  
Cohort 1b: Twelve-month regimen: six doses at 10 mg/kg on Baseline/Day 0 and Weeks 8, 16, 24, 32, and 40. 
All participants will also receive a standardized prednisone taper, starting at either 40 mg orally daily or 30 mg orally 
daily based on doses received during the screening period (see 7.1.1.3). This will be tapered to discontinuation over a 
10-week period. 
 
The schema for Part 1 is shown below (Figure 4). 
 
Figure 4. Trial Schema, Part 1 
 
Immunosuppressive Treatment During the Screening Period 
It is anticipated that some participants will be on immunosuppressive treatment and/or prednisone during the 
screening period. Based on the investigator’s judgement, participants who present with aggressive disease or who 
require a higher starting dose of prednisone because of a large body mass index may be placed on up to 60 mg 
prednisone daily during the screening period. The dose will need to be decreased to 40 mg prednisone /day by the 
baseline visit.     
Prednisone Dosing  
Participants in Part 1 will begin dosing with prednisone on the day of their first elotuzumab infusion. The ten-week 
dosing taper is described in Section 7.1.1.3. 
 


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Sampling for Mechanistic Studies in Part 1A.  All participants in Part 1A will undergo blood sampling for mechanistic 
studies beyond routine flow cytometry at the following time points: 
• 
Baseline/Day 0 
• 
Two days after the first infusion 
• 
Day 7 
• 
Weeks 5, 16, 24 and 48 
Sampling for Mechanistic Studies in Part 1B.  All participants in Part 1B will undergo blood sampling for mechanistic 
studies beyond routine flow cytometry at the following time points: 
• 
Baseline/Day 0 
• 
Weeks 8, 16, 24, 32, 40 and 48 
 Participants will be followed for a total study period of up to 48 weeks.  
3.1.2 
Transition to Part 2 
Once the last participant in Cohort 1b has completed the week 48 visit, a Safety Review Committee (SRC) review will 
be performed to determine the safety of moving to Part 2 of the trial as described in Section 12.11.2. If the SRC 
determines the longer duration of elotuzumab is safe, the twelve-month dosing regimen will be used in Part 2. If 
there are safety concerns with the longer regimen of elotuzumab, the SRC may make recommendations for protocol 
revision.  
3.1.3 
Part 2: Randomized Phase   
Part 2 will enroll a total of 63 participants. Part 2 is a randomized double blind, placebo-controlled trial. Sixty-three 
participants will be enrolled and randomized in a 2:1 ratio to two treatment arms. Arm A:  approximately 42 
participants will be randomized to receive elotuzumab; Arm B: approximately 21 participants will be randomized to 
receive placebo elotuzumab. It is anticipated that the twelve-month regimen from Part 1 will be used for the 
elotuzumab/placebo elotuzumab dosing schedule provided there is no safety signal detected. All randomized 
participants will receive a standardized prednisone taper starting at either 40 mg orally daily or 30 mg orally daily 
based on doses received during the screening period (see 7.1.1.3). This will be tapered to discontinuation over a 10-
week period. The trial schema for Part 2 is shown in Figure 5, below.   
 
 


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Figure 5. Trial Schema, Part 2 
 
Immunosuppressive Treatment During the Screening Period 
It is anticipated that some participants will be on immunosuppressive treatment and/or prednisone during the 
screening period. Based on the investigator’s judgement, participants who present with aggressive disease or who 
require a higher starting dose of prednisone because of a large body mass index may be placed on up to 60 mg 
prednisone daily during the screening period. The dose will need to be decreased to 40 mg prednisone /day by the 
baseline visit.   
Prednisone Dosing  
Participants in Part 2 will begin dosing with prednisone on the day of their first /placebo elotuzumab infusion. The 
ten-week dosing taper is described in Section 7.1.1.3. 
Sampling for Mechanistic Studies in Part 2.  All participants in Part 2 will undergo blood sampling for mechanistic 
studies beyond routine flow cytometry at the following time points: 
• 
Baseline/Day 0 
• 
Weeks 8, 16, 24, 32, 40 and 48 
3.1.4 
Study Duration 
The rate of recruitment to AIG01 is anticipated to be 0.5 participants per week.  
• 
The duration target for Part 1A prior to initiation of Part 1B is 21 weeks (12 weeks of recruitment, 9 weeks of 
follow-up). 
• 
The duration target for Part 1B prior to initiation of Part 2 is 60 weeks (12 weeks of recruitment, 48 weeks of 
follow-up). 
• 
The duration target for Part 2 is 176 weeks (128 weeks of recruitment, 48 weeks of follow-up). 
The total study duration is estimated to be 257 weeks (approximately 5 years). 
 
 


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3.2 Primary Endpoints 
Part 1: Primary Safety Endpoint 
The proportion of participants in each cohort who experience at least one Grade 3 or higher adverse event during study 
participation.   
Part 2: Primary Efficacy Endpoint 
Disease response at 48 weeks, defined as percent improvement in the IgG4-RD RI score over baseline.  
3.3 Secondary Endpoints 
Part 2: Key Secondary Efficacy Endpoint 
1. Complete remission at 48 weeks, defined as an IgG4-RD RI Score of 0 and a glucocorticoid dose of 0 mg/day and 
no flare since beginning treatment. 
Part 1 and Part 2: Additional Secondary Efficacy Endpoints  
1. The proportion of participants that reach the following threshold levels of IgG4-RD RI improvement at 48 weeks:  
50% and 75%. 
2. Number of disease flares, as defined in Section 3.5.3.   
3. Change in PhGA from baseline. 
4. Change in PGA from baseline. 
5. Disease-related damage, as measured by the damage section of the IgG4-RD RI. 
 
Part 1 and Part 2: Secondary Safety Endpoints  
1. The proportion of participants who experience at least one Grade 2 or higher adverse event.  
2. The proportion of participants with a Grade 3 or higher infection. 
3. The proportion of participants who experience a malignancy. 
4. The proportion of participants who experience a Hepatotoxicity, defined as increase in the aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) to elevations three times the upper limit of normal.  
5. The proportion of participants who experience a serious adverse event.  
6. The proportion of participants who experience infusion reactions, defined as any adverse reaction within 24 
hours of infusion which are Grade 2 or higher events and at least possibly related to study drug. 
Part 2: Secondary Safety Endpoint  
1. The proportion of participants who experience at least one Grade 3 or higher adverse event.  
3.4 Exploratory Endpoints 
Part 1 and 2: Exploratory Endpoints 
1. Serum immunoglobulin levels, IgG subclass concentrations, IgE levels, eosinophils, and serum C3 and C4 levels. 
2. ELF score (see 3.5.7). 
3. Blood concentrations of T cells and B cell subsets of interest, specifically:  
a. CD4+ cytotoxic T lymphocytes 
b. CD8+ cytotoxic T lymphocytes 
c. CD4+ T follicular helper cells 
d. CD4+ peripheral helper T cells 
e. Plasmablasts 
f. Activated B cells, including double-negative (CD19+IgD-CD27-) B cells 


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4. Comparison of the kinetics of cell depletion induced by the addition of elotuzumab versus placebo to prednisone 
on disease-associated, SLAMF7-expressing lymphocyte subpopulations, including CD4+ cytotoxic T cells and 
activated B cells, including plasmablasts.   
5. Comparison of elotuzumab and placebo with regard to the impact of the tissue concentrations of CD4+ cytotoxic 
T cells and activated B cells subsets of interest, pre- and post-treatment submandibular gland biopsies.  
6. Correlation of the clonally-expanded effector subset (CD57+CD28-) of CD4+CTLs with disease activity. 
7. Correlation of soluble plasma SLAMF7 levels with disease activity and risk of relapse.    
8. SF-36 health survey.    
3.5 Description of Outcome Variables and Instruments 
3.5.1 
American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification 
Criteria 
The 2019 ACR/EULAR Classification Criteria for IgG4-RD [30, 31] will be used as part of the Inclusion Criteria.  These 
criteria were developed by an international, multi-specialty collaboration of 86 physicians.  Investigators used 
consensus exercises, existing literature, derivation and validation cohorts of 1,879 participants (n=1,086 cases, n=793 
mimickers), and multi-criterion decision analysis to identify, weight, and test potential classification criteria. There 
are three steps to classification. First, a potential IgG4-RD case must demonstrate involvement of at least one of 
eleven possible organs in a manner consistent with IgG4-RD.  Second, Exclusion Criteria consist of a total of 32 
clinical, serological, radiological, and pathological items which, if present, eliminate the participant from IgG4-RD 
classification.  Third, eight weighted Inclusion Criteria domains address clinical findings, serologic results, radiology 
assessments, and pathology interpretations. A sample assessment form is included in Appendix 2: ACR/EULAR. 
Investigators will obtain the biopsy reports from tissue biopsies previously performed for diagnosis. 
3.5.2 
IgG4-RD Responder Index 
The IgG4-RD RI is based on the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [32], utilized for 
the evaluation and licensure of rituximab in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [33]. 
The IgG4-RD RI detects change in disease activity and identifies improvements and worsening in the same or 
different organ systems. The IgG4-RD RI has been used in prior clinical trials to monitor IgG4-RD disease activity [11, 
18, 34]. 
During Part 1A, disease activity will be measured by the IgG4-RD RI at Screening, Baseline/Day 0 if necessary, and at 
Week 24. During Part 1B and 2, disease activity will be measured by the IgG4-RD RI at Screening, Baseline/Day 0 if 
necessary, and at Week 48. The IgG4-RD RI does not need to be repeated at Baseline unless there has been a change 
in Prednisone or other DMARD or if there has been an apparent change in disease activity between Screening and 
Baseline. The RI will also be measured at any interim visit conducted because of the possibility of recurrent disease or 
for the purpose of assessing a potential AE.  
Imaging required to complete a full IgG4-RD RI assessment will be performed at the Screening visit. Specifically, all 
participants will undergo either a CT or MRI of the chest, abdomen, and pelvis within 6 weeks of the Screening visit. 
Participants with clinical evidence of orbital disease will also undergo CT or MRI of that area. If abnormalities in a 
particular area are detected at Screening, the participant will have the same type of study repeated at Week 24 (Part 
1A)  or Week 48 (Part 1B and 2) unless there are contraindications to use of the same imaging technique. Imaging at 
Week 24 (Part 1A) and Week 48 (Part 1B and 2) will be performed if there is a clinical reason to suspect disease 
activity at that site. Imaging may also be repeated at the discretion of the investigator at a visit other than those two 
time points if required to assess disease activity because of a potential disease flare or to assess an adverse event. If 


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participants have received prednisone or another glucocorticoid agent for a total of more than 21 days in the interval 
between the time of qualifying imaging and the Screening visit, the imaging will be repeated at Screening. 
An assessment of damage caused by IgG4-RD in each affected organ is part of the RI. Activity and damage are 
considered separately from the standpoint of scoring, because only disease activity can be expected to respond to 
treatment. A sample assessment form is included in Appendix 3: IgG4-RD RI. 
3.5.3 
Disease Flare Definition 
Disease flare will be defined as recurrence of disease activity such that additional immunosuppressive therapy 
beyond the trial protocol is indicated.  Such additional therapy may include glucocorticoids or alternative 
immunosuppressive agents.  At the time of a potential disease flare, investigators will document the features of the 
disease flare by performing the assessments outlined in the Flare Documentation Guidance (Appendix 5: Flare 
Documentation Guide). A disease flare must be reported by the site investigators to the Division of Allergy, 
Immunology, Transplantation – Statistical and Clinical Coordinating Center (SCCC) within 24 hours of discovery 
(Section 12.5.2). 
3.5.4 
Physician and Patient Global Assessment Visual Analog Scale (VAS) 
The PhGA of the participant’s current disease activity is recorded on a 100 mm linear horizontal VAS, where the left 
hand extreme of the line is considered “Very Good” (symptom free and no IgG4-RD symptoms) and the right hand 
extreme is considered “Very Bad” (maximum IgG4-RD activity).  Only active disease (as opposed to damage) is 
considered in the scoring of the PhGA.  The PGA of current disease activity will be assessed on an identical VAS. 
During Part 1A, assessments will be performed at Screening, Baseline/Day 0, Weeks 1, 5, 9, 16, 24 and 48, as well as 
at any interim visit conducted because of the possibility of recurrent disease or for the purpose of assessing a 
potential AE. During Part 1B and 2, assessments will be performed at Screening, Baseline/Day 0, Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, and 48, as well as at any interim visit conducted because of the possibility of recurrent 
disease or for the purpose of assessing a potential AE. A sample assessment form is included in Appendix 4: PhGA 
and PGA VAS. 
3.5.5 
Flare Guidance Document  
The Flare Guidance Document (FGD) provides guidance with regard to the evaluation of potential disease flares and 
outlines appropriate work-ups for IgG4-RD activity in each organ. Investigators will complete a disease activity 
assessment only in the organs involved in the flare.  The suggested laboratory evaluation, radiology studies, and 
other procedures (e.g., biopsy) as well as the minimum criteria for diagnosis of a disease flare are provided for each 
organ system. Following the documentation of evidence supporting a flare in a given organ, the investigator will 
complete a short narrative justifying the diagnosis of a flare in that organ.  A sample assessment form is included in 
Appendix 5: Flare Documentation Guide. 
3.5.6 
36-Item Short Form (SF-36) Health Survey 
The SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. It has been used in many 
diseases to assess the participant’s perspective of the effect that the disease plays in their activities of daily life. 
These measures rely upon participant self-reporting and are now widely utilized. During Part 1A, this assessment will 
be performed at Baseline/Day 0 and on Weeks 5, 16, 24 and 48. During Part 1B and 2, this assessment will be 
performed at Baseline/Day 0, Weeks 8, 16, 24, 32, 40, and 48. A sample assessment form is included in Appendix 6: 
SF-36 Health Survey. 
 


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3.5.7 
ELF Score 
The ELF score is a set of serological biomarkers consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-
terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA) that shows good correlations with 
fibrosis within organs. During Part 1A, this assessment will be performed at Baseline/Day 0 and on Weeks 5 and 24. 
During Part 1B and 2, this assessment will be performed at Baseline/Day 0 and at Week 8, 16, 24, 32, and 40. 
3.6 Criteria for Evaluation 
3.6.1 
Disease Activity 
The following disease activity parameters will be recorded at scheduled intervals throughout the study: 
• 
IgG4-RD RI Activity Score  
• 
Physician Global Assessment of Disease Activity VAS  
3.6.2 
Disease-Related Damage  
• 
IgG4-RD RI Damage Score 
3.6.3 
Patient-Reported Outcomes 
• 
SF-36 
• 
Patient Global Assessment VAS 
3.6.4 
Safety 
The following safety parameters will be recorded at regular intervals during the study: 
• 
All adverse events using the grading criteria described in Section 12.3.1 
• 
Clinical laboratory testing (clinical chemistry, hematology, and urinalysis)  
• 
Concomitant medications: Any medication related to IgG4-RD taken at any point should be recorded. Other 
non-IgG4-RD related concomitant medications taken 30 days prior to screening through study completion or 
termination should be reported. 
3.6.5 
Serologic Indicators of Response 
• 
Immunoglobulin levels 
• 
IgG subclasses 
• 
IgE 
• 
Eosinophil levels 
• 
C3 and C4 levels 
• 
ELF score  
3.6.6 
Mechanistic Studies 
Mechanistic studies will be conducted at the Ragon Institute of Harvard, Massachusetts General Hospital (MGH), 
Massachusetts Institute of Technology (MIT), and at Emory University.   
Briefly, PBMCs and plasma will be isolated and frozen from each participant on the following schedules. During Part 
1A, samples will be collected at Baseline/Day 0 and then two days after the first elotuzumab infusion. Subsequent 
samples will also be obtained at 1, 5, 16, 24 and 48 weeks, corresponding with clinical blood draws. During Part 1B 
and 2, samples will be collected at Screening or Baseline/Day 0 and Weeks 8, 16, 24, 32, 40 and 48, corresponding 
with clinical blood draws. Mechanistic assessments should not be collected at Screening if the participant is taking 
glucocorticoids on the day of the Screening Visit. If Mechanistic Assessments were not collected at the Screening 


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Visit, they must be collected at Baseline/Day 0. PBMCs and plasma will be stored in liquid nitrogen for preservation. 
The following experiments will be carried out in batches of 10 participant time points per experiment: 
1. 
Flow cytometric quantification of plasmablasts, activated B cells, terminally differentiated CD4+CTLs, terminally 
differentiated CD8+CTLs, activated TFH cells, and peripheral helper T (TPH) cells. Terminal differentiation will be 
defined by the loss of CD28 surface expression and gain of CD57 surface expression within the respective 
effector (CD45RA-CCR7-) T cell population. These cell populations will be assessed on the schedules noted above  
to determine the treatment effect on the absolute numbers and proportions of these cell types. 
2. 
Quantified cell populations will be analyzed for correlation with one another, disease activity, plasma IgG4 levels 
and clinical responsiveness to elotuzumab. 
3. 
Participants with known expansions of the respective cell type and clinical responsiveness to elotuzumab, 
terminally differentiated CD4+CTLs, terminally differentiated CD8+CTLs, and activated B cells will be sorted by 
fluorescence-activated cell sorting (FACS) at weeks 0, 16, 24, and 48. RNA will be isolated to undergo reverse 
transcription polymerase chain reaction (RT-PCR) amplification of the TCR-β/IgH. Next-Generation Sequencing 
will be used to define the diversity of the T cell receptor/B cell receptor (TCR/BCR) repertoire longitudinally to 
ascertain how elotuzumab may impact clonality. 
Mechanistic studies will also be performed on a subset of participants (MGH participants only) with submandibular 
gland involvement at baseline who consent to follow-up submandibular gland biopsies.  Biopsies for 
immunohistochemical studies will be performed using standard core needle biopsy techniques. The purpose of these 
studies will be to determine the effects of study therapy on the chronic inflammatory response at a site of tissue 
inflammation in submandibular glands. For Part 1A, submandibular gland samples will be obtained prior to 
Baseline/Day 0 and between Weeks 16 and 24 following the Baseline/Day 0 visit. For Part 1B and 2, submandibular 
gland samples will be obtained prior to the Baseline/Day 0 Visit, following eligibility confirmation ,and between 
Weeks 40 and 44 following the Baseline/Day 0 visit. Paraffin-embedded sections will be stained with antibodies to 
identify T cells, B cells, macrophages, dendritic cells, cytokines, and chemokines.  
3.7 Stratification, Randomization, and Blinding/Masking 
In Part 2, after participants sign the consent form, those eligible will be randomized in a 2:1 ratio to receive elotuzumab 
versus placebo.  Randomization will be stratified by whether participants have newly-diagnosed or relapsing disease at 
entry.    
Randomization will be accomplished through a password-protected, web-based, randomization system. The 
investigators, clinic personnel, and participants will not be informed regarding the intervention assignment until the 
study is unblinded. Laboratories performing assays for this protocol will be masked to the identity and group assignment 
of biological materials to be studied. 
3.7.1 
Procedure for Unblinding/Unmasking 
Procedures for unblinding are only applicable for Part 2. Unblinding before the study is completed will occur only if a 
participant’s well-being is threatened and the site investigator believes unblinding is necessary for the participant’s 
safety. Unblinding may also occur in the event of pregnancy in a female participant or a male participant’s partner. 
Whenever possible, before treatment assignment for an individual participant is unblinded, the site investigator must 
confer with the National Institute of Allergy and Infectious Diseases (NIAID) medical monitor and the protocol chair. If 
emergency unblinding is required for a participant’s well-being during non-business hours, the site principal 
investigator or designee (i.e., sub-investigator specified on Form FDA 1572) must notify the investigative pharmacy of 
the need for the treatment assignment. A full account of the event will be recorded, including the date and time of 


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the emergency, the reason for the decision to unblind, and the names of those notified/consulted with. The site 
investigator will notify the protocol chair and the study Statistical and Clinical Coordinating Center of the unblinding 
event on the next business day. The emergency unblinding will be reported to the Data and Safety Monitoring Board 
(DSMB). The reasons for unblinding of a participant’s treatment assignment will be included in the final study report 
to the FDA. 
Unblinding of treatment assignments for an individual participant or subgroups of participants for planned or 
unplanned interim analyses to support DSMB reviews will require NIAID approval. Study-derived Investigational New 
Drug (IND) Safety Reports will be reported to the FDA, DSMB, and Institutional Review Board (IRB) in an unblinded 
fashion as per International Conference for Harmonisation (ICH) and local guidance after approval by the NIAID 
medical monitor. 
4 Selection of Participants  
4.1 Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for enrollment as study participants:  
1. Participant must be able to understand and provide informed consent and be willing to comply with study 
procedures and follow up.  
2. Are at least 18 years of age and not older than 70 years of age at screening.    
3. Meet the ACR/EULAR Classification Criteria for IgG4-RD [30, 31]. 
4. Have active disease based at screening on an IgG4-RD RI ≥4, with disease manifestations in at least two organ 
systems. 
5. May have newly-diagnosed or relapsing disease at screening. Relapsing disease is defined as IgG4-RD that has 
previously been in remission but is now active again.     
6. May be on treatment or off treatment for IgG4-RD at the time of screening. If on treatment, must be willing to 
discontinue those other treatments before the baseline visit.  
7. No history of severe allergic reactions to monoclonal antibodies.   
8. Female participants of childbearing potential must have a negative pregnancy test upon study entry. 
9. Female participants of childbearing potential and male participants with a partner of childbearing potential must 
agree to consistently and correctly use FDA approved highly effective methods of birth control, as shown in 
Appendix 8: Acceptable Contraception Methods for Females of Reproductive Potential, for the entire duration 
of the study and 6 months after last elotuzumab infusion. 
10. Immunization with one of the FDA authorized or licensed SARS-CoV-2 vaccines as per CDC recommendations at 
the time of informed consent is required for study entry. Vaccinations must have been completed at least 2 
weeks prior to start of study therapy.1 
4.2 Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment as study participants:   
1. Presence of a condition other than IgG4-RD that (e.g., asthma) is likely to require systemic Glucocorticoids (GC) 
for disease control during the period of the trial. 
 
1 Vaccination status must conform to CDC recommendations for immunocompromised individuals. These recommendations are subject to change, 
but are updated at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html. 


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2. Malignancy within 5 years (except successfully treated in situ cervical cancer, resected squamous cell or basal 
cell carcinoma of the skin.) 
3. The following lab values as indicators of hepatic dysfunction:  
a. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times the 
upper limit of normal (ULN) 
b. Total bilirubin > two times the ULN unless caused by Gilbert’s disease. Gilbert’s disease with total 
bilirubin > three times ULN. 
c. Serum albumin < 2.5 gm/dL. 
4. Evidence of another uncontrolled condition which, in the judgment of the investigator, could interfere with 
participation in the trial according to the protocol. 
5. Active infection requiring hospitalization or treatment with systemic antimicrobial agents within the 30 days 
prior to treatment allocation/randomization. 
6. Prior use of rituximab or other B cell depleting agents within 9 months of enrollment unless B cells have been 
demonstrated to have repopulated. 
7. Use of any investigational agent or biologic and non-biologic DMARDs within 5 half-lives of the agent (or 6 
months if the half-life is unknown) prior to enrollment. 
8. Any of the following laboratory tests at the Screening Visit: 
a. White blood cell count (WBC) < 3.0 x 103/µL. 
b. Absolute neutrophil count (ANC) < 1.5 x 103/µL. 
c. Hemoglobin < 10 g/dL. 
d. Platelet count < 75 x 109/L. 
e. Estimated glomerular filtration rate (eGFR) ≤ 45 ml/minute/1.73 m2. 
9. The use of supplemental oxygen at baseline. 
10. At or within 90 days of screening: Positive Interferon-Gamma Release Assay (IGRA). Indeterminate IGRAs must 
be repeated (with same or other IGRA per local policy) and shown to be negative. Alternatively, if the assay 
remains indeterminant, a participant must have a negative PPD. Finally, if the participant has had the Bacille 
Calmette-Guerin (BCG) vaccine or has some other condition complicating the interpretation of TB testing, 
consultation with infectious disease specialist must be obtained before receipt of the first investigational 
infusion.  
a. Participants diagnosed with latent TB are eligible but must have received appropriate prophylaxis for 30 
days before their first investigational infusion.  
11. Medical history or serologic evidence at Screening of chronic infections including: 
a. Human immunodeficiency virus infection.  
b. Hepatitis B as indicated by surface antigen or hepatitis B core antibody positivity  
c. Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody 
positive, they will be eligible to participate in the study if he/she is negative for viral load at Screening. 
12. Live vaccines within 8 weeks of initiating study therapy.  
13. Participant is pregnant or breastfeeding, or planning a pregnancy while enrolled in the study. 
14. Substance use disorder, including the recurrent use of alcohol and/or drugs within the past year associated with 
clinically significant impairment associated with failure to meet major responsibilities at work, school, or home. 
15. IgG4-RD that is dominated primarily by advanced fibrotic lesions.  Specifically, participants whose disease 
manifestations consist only of  
a. retroperitoneal fibrosis,  
b. fibrosing mediatinitis,  


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c. sclerosing mesenteritis, or  
d. Riedel’s thyroiditis.   
Participants with these disease manifestations can be included, however, only if they have disease in 2 
organ systems that is not of an advanced fibrotic nature and otherwise meet the Inclusion and Exclusion 
Criteria.  
16. Evidence a SARS-CoV-2 (COVID-19) infection started within the 30 days prior to treatment 
allocation/randomization. Participants diagnosed with SARS-CoV-2 (COVID-19) infection more than 30 days prior 
to treatment allocation/randomization must have symptoms resolved and be deemed fit to participate in the 
trial. 
 
4.3 Co-enrollment Guidelines 
While participating in AIG01, participants may not be in another interventional trial, but may be in observational 
registries or cohorts as long as the total combined volume of blood to be drawn does not exceed the National Institutes 
of Health (NIH) limit of and objectives do not confound the current study. 
5 Known and Potential Risks and Benefits to Participants 
5.1 Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert 
Common risks include infusion reactions, immunogenicity, and infections.   
5.1.1 
Infusion Reactions 
Elotuzumab can cause infusion reactions. The infusion reactions associated with elotuzumab are mitigated with a 
standard premedication regimen. 
Infusion reactions were reported in approximately 10% of participants treated with elotuzumab, lenalidomide, and 
dexamethasone (Study CA204004); in 5.4% of participants treated with elotuzumab, bortezomib, and 
dexamethasone (Study CA204009); and in 2.5% of participants treated with elotuzumab, lenalidomide, and 
dexamethasone (Study CA204116). All reports of infusion reaction were ≤ Grade 3.  
Grade 3 infusion reactions occurred in 1.3 % of participants in Study CA204004 and in no participants in Study 
CA204009 or Study CA204116. The most common symptoms of an infusion reaction included fever, chills, and 
hypotension. In Study CA204004, 5% of participants required interruption of the administration of elotuzumab due to 
infusion reactions for a median of 25 minutes and 1% of participants discontinued due to infusion reactions. In Study 
CA204009, 20% of participants required interruption of the administration of elotuzumab for a median of 40 minutes 
but no participants discontinued due to infusion reactions. Of the participants who experienced an infusion reaction, 
70% (23/33) in Study CA204004 and 80% (4/5) in Study CA204009 had them during the first dose. [35-38] 
5.1.2 
Pregnancy & Lactation 
Animal reproduction studies have not been conducted with elotuzumab. It is also not known whether elotuzumab 
can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Elotuzumab is not 
recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the 
clinical benefit outweighs the potential risk. Study participants should be advised to avoid pregnancy while receiving 
treatment with elotuzumab. 


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It is not known whether elotuzumab is secreted into human milk. Published data suggest that antibodies in breast 
milk do not enter the neonatal and infant circulations in substantial amounts. However, because of the potential for 
adverse reactions in nursing infants, a decision should be made whether to discontinue breastfeeding or to 
discontinue from elotuzumab therapy, taking into account the benefit of breastfeeding for the child and the benefit 
of elotuzumab therapy for the woman. 
5.1.3 
Infections 
The incidence of infections, including pneumonia, was higher with elotuzumab treatment than with controls. In the 
largest clinical study of elotuzumab in participants with multiple myeloma, Study CA204004; N = 635), infections 
were reported in 81.4% of participants in the elotuzumab/lenalidomide arm and 74.4% in the lenalidomide arm. 
Grade 3 to 4 infections were noted in 28% and 24.3% of elotuzumab/lenalidomide-treated participants and 
lenalidomide-treated participants, respectively. Fatal infections were infrequent, reported in 2.5% of the 
elotuzumab/lenalidomide group and 2.2% of the lenalidomide group.   
In the same trial (CA204004) opportunistic infections occurred in 22% of participants in the elotuzumab/ 
lenalidomide arm and in 13% of participants in the lenalidomide arm.  Fungal infections occurred in 10% of the 
participants in the elotuzumab/ lenalidomide arm and 5% of participants in the lenalidomide arm. Herpes zoster 
occurred in 14% of the participants in the elotuzumab/lenalidomide arm and 7% of participants in the lenalidomide 
arm. 
Elotuzumab may also increase the risk of SARS-CoV-2 (COVID-19) infections. This is because of the drug’s broad 
effects on B-lymphocytes as well as CD4+ and CD8+ T-lymphocytes and NK cells. As of the date of this amendment, 
Bristol-Myers Squibb has not recognized a safety signal in COVID-19 infection in their worldwide safety database 
(personal communication). In view of the worldwide surge in SARS-CoV-2 (Omicron variant) infections in the winter 
of 2021-2022, the AIG01 protocol was adjusted accordingly as described in section 6.4.2: Toxicity Prevention & 
Management.   
5.1.4 
Hepatotoxicity 
In study CA201004, elevations in liver enzymes greater than 3 times the ULN and total bilirubin greater than 2 times 
the ULN and alkaline phosphatase less than 2 times the ULN consistent with hepatotoxicity were see in 2.5% of 
participants in the elotuzumab/ lenalidomide arm and 0.6% of participants in the lenalidomide arm. Two of the 8 
affected participants were not able to continue treatment with elotuzumab. No meaningful difference in hepatic 
function tests between the arms was reported. 
IgG4-RD seldom affects hepatocytes directly. Abnormalities of the liver noted in IgG4-RD are usually the result of 
biliary tract disease.  We do not anticipate, therefore, an increased propensity to liver injury among the IgG4-RD 
participants in this trial.   
5.1.5 
Malignancies 
There are no consistent reports of the use of elotuzumab associated with the development of secondary 
malignancies in the setting of individuals treated for multiple myeloma. However, in study CA204004, invasive 
secondary primary malignancies were observed in 12.3% of participants in the elotuzumab/ lenalidomide arm and 
8.8% of participants in the lenalidomide arm. 
5.1.6 
Immunogenicity (Anti-Elotuzumab Antibodies)  
There is a potential for immunogenicity to elotuzumab. Of 390 participants across 4 clinical studies who were treated 
with elotuzumab and were evaluable for the presence of anti-product antibodies, 72 (18.5%) participants tested 


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positive for treatment-emergent anti-product antibodies by an electrochemiluminescent assay. Neutralizing 
antibodies were detected in 19 of 299 participants in Study CA204004. In the majority of participants, 
immunogenicity started early, was transient, and resolved by 2 to 4 months. There was no clear causal evidence of 
altered protein kinase (PK), efficacy, or toxicity profiles with anti-product antibody development.   
5.1.7 
Other Frequently-reported Adverse Events 
The most common AEs (≥ 40%) were diarrhea (67.1%), muscle spasms (61.6%), fatigue (57.5%), constipation (50.7%), 
nausea (47.9%), upper respiratory tract infection (46.6%), pyrexia (42.5%), back pain (42.5%), and anemia (41.1%). 
The majority of these were Grade 1 or 2 in severity. Grade 3 to 4 treatment emergent adverse events (TEAEs) were 
reported in 57 (78.1%) participants. The most common (≥ 10%) were lymphopenia (19.2%), neutropenia (19.2%), 
thrombocytopenia (17.8%), anemia (15.1%), and pneumonia (11.0%). SAEs reported in more than 2 participants were 
pneumonia (12.3%), sepsis (6.8%), and bronchitis, cellulitis, and febrile neutropenia (4.1% each). 
5.2 Risks of Other Protocol Specified Medications 
5.2.1 
Corticosteroids 
Corticosteroids (prednisone and methylprednisolone) can be associated with weight gain, glucose intolerance, 
increases in blood pressure, insomnia, mood swings, glaucoma, cataracts, an increase in the risk of infection, skin 
toxicity (including acne, hirsutism, easy bruisability, skin tears, and striae) and adverse effects on bone mineral 
density.  
Premedications are administered before each elotuzumab infusion. These premedications are: 
1. Methylprednisolone 50 mg 
2. Diphenhydramine 25-50 mg 
3. Acetaminophen 650 mg 
4. H2 blocker: famotidine (20 mg intravenously or orally) or equivalent H2 blocker. 
Diphenhydramine can be associated with somnolence, drowsiness, impairment of mental functioning, dry mouth, 
inability to urinate, and constipation. 
Acetaminophen can be associated with rash, nausea, headache, hypersensitivity, serious skin reactions, kidney and 
liver damage. 
5.3 Risks of Study Procedures  
5.3.1 
Risks Specific to Imaging and Contrast Material  
Oral or intravenous contrast agents may be used in some radiology studies. The Iodine-based and barium-sulfate 
compounds may be used for CT scans, with gadolinium the contrast material used for MRI.  Risks of contrast include 
allergic reaction, and rarely anaphylaxis. A careful history regarding risk factors must be assessed. Individuals with 
history of asthma or allergy to contrast dye, iodine, or shellfish may not be suitable candidates for the procedure. 
Additionally, impaired renal function may be a contraindication for contrast material. Iodine-based contrast materials 
pose risk of contrast-induced nephropathy, with worsening of pre-existing renal impairment. Nephrogenic systemic 
fibrosis, a thickening of the skin, organs, and other tissues, is a rare complication in individuals with renal disease 
undergoing MRI with contrast material.  
The need for contrast agents will be reviewed on an individual basis, consistent with the routine use of these imaging 
studies and individual risk assessment. Consultation with radiology will be obtained as needed. 


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5.3.2 
Risks Specific to CT Scan 
The total amount of radiation for the two CT scans is approximately 12 milliSieverts (mSv). Participants entering the 
study who have undergone recent CT scan may alternatively have MRI for study baseline establishment. If no 
abnormalities are detected at Screening/baseline on imaging of the chest/abdomen/pelvis, then the Weeks 24 and 
48 imaging study can be an MRI (in the interest of reducing exposure to ionizing radiation from CT).  
5.3.3 
Risks Specific to MRI 
A careful history regarding any of the following contraindications for MRI will be obtained:  
• 
Implanted pacemakers 
• 
Intracranial aneurysm clips 
• 
Cochlear implants 
• 
Certain prosthetic devices 
• 
Implanted drug infusion pumps 
• 
Neurostimulators 
• 
Bone-growth stimulators 
• 
Certain intrauterine contraceptive devices; or 
• 
Any other type of iron-based metal implants. 
MRI is also contraindicated in the presence of internal metallic objects such as bullets or shrapnel, as well as surgical 
clips, pins, plates, screws, metal sutures, or wire mesh. Pregnancy is an exclusion for the procedure and study as a 
whole.  
MRI is contraindicated for individuals with epilepsy. Additionally, a history of claustrophobia and anxiety with 
previous MRI must be considered as a possible contraindication. 
5.3.4 
Risks with Peripheral Intravenous Catheters 
The placement of peripheral intravenous catheters can be associated with pain, bleeding, ecchymosis, peripheral 
nerve injury, and infection. Only medical personnel trained and proficient in the placement and management of 
venous access devices will perform this function in the study. 
5.4 Potential Benefits 
IgG4-RD is a recently-described disease for which no approved therapy exists. IgG4-RD causes important end-organ 
damage, including failure of both the exocrine and endocrine pancreas (autoimmune pancreatitis); hepatic failure 
(cholangitis); kidney failure from intrinsic renal disease (tubulointerstitial nephritis); obstructive nephropathy and 
chronic pain (retroperitoneal fibrosis); dysfunction of other organs (orbits, lung); and death from a variety of causes 
(complications of aortitis, pulmonary disease, meningeal involvement, other).  Prednisone is an effective therapy in 
many participants but does not cure the disease, nor does it lead to sustained, treatment-free remissions in most 
participants.  Moreover, the use of glucocorticoids in a disease that affects a middle-aged to elderly population and has 
a predilection for causing exocrine insufficiency of the pancreas is problematic. Rituximab is a potential alternative 
therapy to prednisone that has not been studied in detail.            
IgG4-RD is an excellent disease model for studying human fibrotic disease.  Certain characteristics of IgG4-RD make it 
an ideal condition through which to explore human immunology and the broad impact of targeting SLAMF7 in human 
fibrotic disease.  First, although recognized only in the past fifteen years, IgG4-RD is in fact relatively common, with an 
estimated prevalence in the U.S. of approximately 186,000 cases – just barely classifiable as an orphan disease. IgG4-RD 
has a worldwide disease distribution and is evaluated by medical subspecialists of nearly every type.   


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Second, IgG4-RD has a clinical phenotype that is now well-recognized.  The 2019 Classification Criteria for IgG4-RD have 
a specificity of 98% and a sensitivity of 83% [30, 31]. 
Third, and perhaps most importantly, IgG4-RD is typically an indolent disease that causes tissue injury over months or 
even years due to unbridled inflammation, myofibroblast activation, cytotoxicity, and fibrosis. The indolence of IgG4-RD 
is crucial to our ability to study disease mechanisms.  The upshot of its indolent nature is that clinical trials in IgG4-RD 
can be designed such that participants are treated with an investigational medication with close monitoring, with little 
or no additional immunosuppression (e.g., glucocorticoids, mycophenolate mofetil, methotrexate).  IgG4-RD therefore 
offers a favorable disease state in which to investigate the impact of a targeted intervention on the immune system 
carefully, without the confounding factor of non-specific immunosuppressive therapies used concomitantly. 
6 Investigational Regimen  
6.1 Elotuzumab and Placebo for Elotuzumab 
6.1.1 
Product Description 
Elotuzumab (BMS-901608) is a humanized recombinant mAb targeted against SLAMF7, a cell surface glycoprotein. 
Elotuzumab consists of the complementarity determining regions of the mouse antibody, MuLuc63, grafted onto 
human IgG1 heavy and kappa light chain framework regions. 
Elotuzumab for injection is provided in 400 mg single-dose vials for reconstitution, dilution, and IV infusion. The drug 
product, a nonpyrogenic lyophilized powder, is a white to off-white, whole or fragmented cake contained in a 20 cc 
Type I glass vial, closed with a 20-mm stopper and sealed with an aluminum seal. Each vial of drug product contains 
the labeled amount of elotuzumab drug substance, sucrose, sodium citrate dihydrate, citric acid monohydrate, and 
polysorbate 80. A 0.8-mL overfill is included in each vial to account for vial, needle, and syringe holdup.  
6.1.2 
Formulation, Packaging, and Labeling 
Elotuzumab (Empliciti®) is a marketed drug and will be provided for the conduct of this study by the manufacturer, 
Bristol-Myers Squibb Co. (BMS). Elotuzumab will be distributed to sites by a designated drug distributor under 
contract with NIAID. 
6.1.3 
Storage Conditions 
Store elotuzumab under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light. Do not freeze or shake.  
6.1.4 
Dosage, Preparation, and Administration 
Part 1  
Participants receive either a 1-month or twelve-month regimen of elotuzumab, depending on enrollment phase (see 
Study Design Section 3). Each intravenous dose will be 10 mg/kg, to be determined based on participant’s weight.  
Rounding is permissible within 5% of the nominal dose.  The participant’s actual weight will be used for dosing. At the 
Baseline/Day 0 visit, the participant’s screening weight will be used for calculation of the Baseline/Day 0 infusion 
dose. For all subsequent infusions, weight from the previous visit will be used unless weight was obtained more than 
42 days previously. If more than 42 days have elapsed since the previous visit, the participant’s current weight will be 
used for calculation.  
The 1-month regimen consists of 4 weekly doses of elotuzumab (10 mg/kg) on days 0, 7, 14, and 21. The twelve-
month regimen consists of 6 doses at Baseline/Day 0, Week 8, Week 16, Week 24, Week 32, and Week 40.  


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Part 2 
Part 2 is a randomized, double-blind, placebo-controlled phase in with participants receive either elotuzumab or 
placebo for elotuzumab in a 2:1 ratio. It is anticipated that the twelve-month regimen from Part 1 will be used for the 
elotuzumab and placebo for elotuzumab dosing schedule, provided there is no safety signal detected. The pharmacist 
is the only site personnel not blinded to the treatment assignment. Placebo for elotuzumab will be investigational 
sites’ stocked 0.9% normal saline prepared by the site pharmacist.  
The oral glucocorticoid regimen for all participants in Part 1 and Part 2 is described in Protocol Section 7.1.1.3. 
6.1.4.1 
Placebo for Elotuzumab  
The placebo for elotuzumab will be 0.9% sterile normal saline for injection. Placebo for elotuzumab will be 
prepared at each site’s investigational pharmacy. Investigational pharmacies will use sterile normal saline 
that is produced by an FDA registered facility as designated by the presence of a National Drug Code (NDC) 
number on product labeling. Product information including manufacturer, lot number, and expiration date 
will be documented on participant-specific accountability log during each preparation and dispensing.  
Placebo for elotuzumab will be given as intravenous infusion bag, volume matched to elotuzumab. More 
detailed information will be included in the pharmacy manual.  
6.1.4.2 
Elotuzumab Administration and Monitoring 
 Pre-medication 
Pre-medicate approximately 45-90 minutes prior to each elotuzumab/placebo infusion with the 
following: 
• 
Methylprednisolone 50 mg intravenously 
• 
Diphenhydramine 25-50 mg orally or intravenously 
• 
Acetaminophen 650 mg orally 
• 
H2 blocker: famotidine (20 mg intravenously or orally) or equivalent H2 blocker 
 Administration 
The infusion is to be administered through a sterile, nonpyrogenic, low protein binding in-line filter (with 
a pore size of 0.2 μm to 1.2 μm) using an automated infusion pump. Initiate infusion at a rate of 0.5 mL 
per minute. The infusion may be increased in a stepwise fashion as described in the table below if no 
infusion reaction. The maximum rate should not exceed 5 mL per minute. 
First Dose 
Second Dose 
Subsequent 
Doses 
Time Interval 
Rate 
Time Interval 
Rate 
Rate 
0-30 min 
0.5 mL/min 
0-30 min 
3 mL/min 
 
5 mL/min 
30-60 min 
1 mL/min 
≥ 30 min 
4 mL/min 
≥ 60 min 
2 mL/min 
--- 
--- 
Elotuzumab must not be administered as an IV push or bolus. Do not mix elotuzumab, or administer as 
an infusion, with any other medicinal products.   
In Part 1A, there must be a minimum of four full days between each weekly infusion. In Part 1B and 2, 
there must be a minimum of seven full days between each infusion. 


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If an infusion is missed for reasons other than those requiring premature discontinuation (Section 6.6), a 
single intermediate delayed infusion may be permitted if it can be administered with the minimum 
windows before the next scheduled infusion that are noted above.  Additional details on toxicity 
management and criteria for the resolution of specific adverse events before restarting infusions are 
given in Section 6.4.    
In Part 1A, if the infusion schedule has been interrupted, administration of infusions may be adjusted to 
permit administration of 4 doses prior to the week 11 visit. In Part 1B and 2, no infusions can be 
administered after Week 44 in order to evaluate the durability of a disease response or complete 
remission at Week 48.    
 Monitoring 
Elotuzumab/placebo infusions will occur in a setting with access to advanced cardiovascular life support 
(ACLS) certified personnel, resuscitative drugs, monitoring devices, and CPR equipment. Vital signs must 
be assessed prior to the infusion, approximately every 15 minutes during the infusion, at the end of the 
infusion, and 1 hour after completion of the infusion or per comparable institutional standards. 
If an infusion reaction occurs, the infusion should be interrupted and medical management instituted as 
needed (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen). See protocol Section 6.4.1 for 
additional guidelines on managing an infusion reaction. 
6.2 Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator will maintain adequate records of the 
disposition of the investigational agent, including the date and quantity of the drug received, to whom the drug was 
dispensed (participant-by-participant accounting), and a detailed accounting of any drug accidentally or deliberately 
destroyed. The investigator will ensure that the investigational product is stored as specified in the protocol and 
pharmacy manual in a secured area within the pharmacy, with access limited to authorized study personnel. For this 
study, these responsibilities are delegated to each site’s Pharmacist of Record (PoR).  
Records for receipt, storage, use, and disposition will be maintained by the study site.  A drug-dispensing log will be kept 
current for each participant.  This log will contain the identification of each participant and the date and quantity of drug 
dispensed. All remaining unused investigational product will be returned to the sponsor or sponsor’s representative 
after study termination. 
All records regarding the disposition of the investigational product will be available for inspection. 
6.3 Assessment of Participant Dosing Compliance  
Elotuzumab/placebo will be administered intravenously at sites by trained medical staff. Compliance, therefore, will be 
monitored by the site and documented on the electronic Case Report Form (eCRF).  
Dosing compliance with oral prednisone (see Protocol Section 7.1.1.3) will be assessed by pill count at each visit. Study 
personnel will calculate compliance in the presence of the participant so that reinforcement/re-education can be 
conducted as needed.  Drug accountability and compliance will be documented on the source visit record and in the 
electronic data capture system.  
 
 


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6.4 Toxicity Prevention and Management 
6.4.1 
Infusion Reactions 
Infusion reactions in the pivotal studies in multiple myeloma are described in Protocol Section 5.1.1. Pre-medications 
are described in Protocol Section 6.1.4.2.1. In the event of a Grade 2 infusion reaction, suspend the infusion and 
institute appropriate medical and supportive measures per institutional standards.  Upon complete or partial 
resolution (Grade 1), restart elotuzumab/placebo at 0.5 mL/min. Gradually increase infusion rate by 0.5 mL/min 
every 30 minutes as tolerated to the rate at which the reaction occurred. Resume rate escalation regimen (Protocol 
Section 6.1.4.2.2) if there is no recurrence of infusion reaction. 
In the event of an infusion reaction, monitor vital signs at least every 30 minutes for 2 hours after completion of the 
infusion and otherwise as clinically indicated. If the infusion reaction recurs, stop the infusion and do not restart on 
that day. A Grade 3 or higher infusion reaction including anaphylaxis will require permanent discontinuation of 
elotuzumab/placebo.  If anaphylaxis occurs, immediately and permanently discontinue elotuzumab/placebo and 
administer emergency medical therapy. 
6.4.2 
Infection 
Elotuzumab should not be given during periods of active infection. Signs and symptoms of infection that warrant 
investigator consideration to withhold study drug administration include but are not limited to the following: 
• 
Fever > 38° C 
• 
Symptoms of upper/lower respiratory or urinary tract infection 
• 
Vomiting/diarrhea within 24 hours 
Discontinue study drug permanently in the event of a Grade 4 infection.  
Guidance for proceeding with study drug administration following a Grade 3 infection and resolution includes: 
• 
Allowing at least one month between restarting the study drug and start of the infection 
• 
Full recovery of acute symptoms and effects 
• 
Completion of treatments for the infection 
• 
Clinical determination that participant is deemed fit to resume elotuzumab 
Guidance for proceeding with study drug administration following a ≤ Grade 2 infection and resolution includes: 
• 
Improvement/resolution of symptoms 
• 
Resolution of fever for at least 24 hours 
• 
Antibiotic administration for a minimum of 48 hours (as applicable) 
• 
Initial cultures negative at 48 hours (if obtained) unless appropriate antibiotic therapy instituted 48 hours in 
advance of the infusion 
Elotuzumab should not be given if a participant has a positive SARS-CoV-2 (COVID-19) viral test. If a participant 
develops a SARS-CoV-2 (COVID-19) infection, elotuzumab may be resumed one month after start of the infection, 
once the participant has recovered from the infection’s acute symptoms and effects, stopped treatments for the 
infection, including supplemental oxygen, and is deemed fit to resume elotuzumab. Instructions for resuming the 
protocol-specified prednisone taper are detailed in section 7.1.1.3. 
Once the infection resolves, elotuzumab/placebo may be restarted at the next scheduled dose. If the infection 
resolves in time for a delayed infusion to be administered in the minimum window before the next scheduled 
infusion specified in Section 6.1.4.2.2, a single intermediate administration is permitted. In Part 1A, if the infusion 


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schedule has been interrupted, administration of infusions may be adjusted to permit administration of 4 doses prior 
to the week 11 visit.  In Part 1B and 2, no infusions can be administered after Week 40 in order to evaluate the 
durability of a disease response or complete remission at Week 48.    
6.4.2.1 
Varicella Zoster Infection and Reduced Response to Vaccination 
Participants will be informed about the potential for Varicella zoster (herpes zoster) infections. Following a 
discussion with the investigator as part of the consent process, participants who have not received the 
recombinant zoster vaccination (Shingrix®) may elect to receive the first dose of the vaccine prior to 
participating in the study as part of standard of care. In this situation, the second vaccine dose may be 
administered as recommended 4-6 months later, as standard of care and not part of the study. Participants 
will be counseled about the potential effects of elotuzumab on responses to immunization and the need to 
follow up on the status of their immunity with their primary care providers following participation in the 
trial.     
6.4.2.2 
General Principles for Protection from COVID-19  
The following principles guide the conduct of the trial during the COVID-19 public health emergency: 
• 
The safety of participants is paramount. Any decisions to begin, continue, or stop enrollment in 
the study will be made with consideration of the potential impact of COVID-19 on the safety of the 
participants. Trial participants will be kept informed of any changes in the study and any impacts 
on their participation. The nature of the study intervention, a targeted therapy with 
immunosuppressive properties, requires careful monitoring of the study participants and the 
status of the rates of COVID-19 infections at the individual clinical sites. 
• 
The decision to continue or discontinue the experimental intervention will be made with the 
safety and welfare of the trial participant in mind. This decision will be made jointly between the 
sponsor, study chair, site investigator, and Institutional Review Board. Due consideration will be 
given to the fact that elotuzumab/corticosteroids may interfere with the ability of the participant’s 
immune system to produce neutralizing antibodies against SARS-CoV-2 and could significantly 
increase the susceptibility to and severity of infection. 
• 
Participants should be advised to increase their protection from COVID-19 infection by doing the 
following: wearing a well-fitting mask indoors in public in areas or when around others who are 
not up to date on their COVID-19 vaccines or not eligible to receive COVID-19 vaccines, stay 6 feet 
away from others, avoid poorly ventilated spaces and crowds, and wash hands often.  These 
recommendations are subject to change, but are updated at: 
https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html 
• 
In certain cases, the participant may not be able to come to the study site, or local institutional 
policies or other factors may intervene to limit access to the research site. The sponsor in 
consultation with site personnel will determine if alternative methods for assessments are 
necessary and feasible, and will assure the safety of the study participant. For example, in-person 
visits may be substituted with virtual visits or phone contact, or trial participants may come to an 
alternative site for completion of their safety assessments (e.g. off-campus laboratory).  Changes 
in modality/timing of study visits, data collection, and/or other protocol deviations will be 
documented accordingly. 


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• 
Urgent or emergent changes in the protocol as a result of COVID-19 infection or the rising rates of 
COVID infections to protect the safety of participants may be implemented immediately without 
IRB approval, with concurrent notification of the IRB. The sponsor and the investigators will work 
closely with IRB to implement any required changes in the protocol or the consent form, as 
appropriate and submit any revised documents to FDA per current guidance. 
• 
Participants should continue to receive SARS-CoV-2 vaccinations per CDC and FDA 
recommendations during the course of the study. 
• 
Any participant who has close contact with a SARS-CoV-2 infected individual should be evaluated 
for post-exposure prophylaxis as soon as possible after exposure. 
6.4.2.3 
SARS-CoV-2 Prevention  
The AIG01 protocol requires specific measures in the interest of preventing SARS-CoV-2 infections. The 
current and future FDA approval and emergency use authorization of SARS-CoV-2 vaccines and updates to 
CDC recommendations on vaccinations programs to promote public health may impact the enrollment and 
monitoring of trial participants. The sponsor in consultation with the investigators will determine if any 
protocol modifications are necessary as the situation evolves. Vaccine immune response may be blunted by 
treatment with corticosteroids and elotuzumab. 
Specific measures designed to prevent SARS-CoV-2 infections include: 
• 
Participants must be confirmed negative for SARS-CoV-2 by antigen test within 24 hours of each 
infusion. Participants will be provided antigen tests by the site, test themselves, and provide proof 
of negativity. 
6.4.3 
Hepatotoxicity 
IgG4-RD seldom affects hepatocytes directly. Abnormalities of the liver noted in IgG4-RD are usually the result of 
biliary tract disease.  We do not anticipate, therefore, an increased propensity to liver injury among the IgG4-RD 
participants in this trial. Nevertheless, the eligibility criteria have been written conservatively to exclude participants 
with significant risk-factors for hepatic insult. Liver function tests will be monitored frequently prior to infusions with 
elotuzumab/placebo and throughout the follow-up period to assess for potential drug-induced liver injury, with 
particular concern for hepatic transaminase elevation and hyperbilirubinemia. The specific laboratory measures of 
concern, which correspond to Grade 3 adverse events, are:  
• 
ALT or AST elevation > 5 times ULN,  
• 
Total bilirubin > 3 times ULN. If Gilbert’s disease, total bilirubin > 3 times baseline value. 
A grade 3 or higher elevation in liver enzymes, defined as ALT or AST > 5 times ULN or a total bilirubin > 3 times the 
upper limit of normal, that persists longer than 5 days will result in discontinuation of elotuzumab/placebo. For a 
grade 3 or higher event that resolves in less than 5 days, elotuzumab/placebo may be restarted under the schedule 
noted in Section 6.4.2. 
6.4.4 
Primary Malignancy 
The eligibility criteria have been written conservatively to exclude individuals with a history of malignancy within 5 
years (except for successfully treated in situ cervical cancer, resected squamous cell or basal cell carcinoma of the 
skin). Given the information on second primary malignancies in the elotuzumab prescribing information, attention 
will be paid to monitoring for malignancy as consistent with standard of care.  


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Participants over the age of 50 should have age-appropriate cancer screenings at the investigator’s discretion prior to 
enrollment and throughout the course of the study. For additional information, consult the American Cancer Society 
(ACS) reference below: http://www.cancer.org/healthy/toolsandcalculators/reminders/screening-
recommendationsby-age  
6.5 Submandibular Gland Biopsy  
During Part 1A, an optional submandibular gland biopsy (MGH participants only) will be performed between screening 
and Baseline/Day 0 and between Weeks 16 and 24 to evaluate the tissue response to study therapy. During Part 1B and 
2, an optional submandibular glad biopsy will be performed prior to the Baseline/Day 0 Visit, following eligibility 
confirmation, and between Weeks 40 and 44. The participants will be instructed to suspend aspirin or NSAID intake 3-7 
days before the procedure. Core needle biopsy of the submandibular gland is generally only slightly painful and rarely 
associated with significant morbidity. However, it is possible that a biopsy site might become infected, requiring 
antibiotic treatment or surgical debridement. The biopsy is done through normal appearing overlying skin. After 
application of a topical anesthetic, local anesthetic with vasoconstrictor is infiltrated into the area around the 
submandibular gland.  An ice pack is then placed on the skin in the area of the biopsy to reduce swelling and bruising 
(risk management). Part of the submandibular gland biopsy will be placed in normal saline for special studies. Part will 
be placed in a neutral buffered formalin for studies using paraffin-embedded sections. The remaining gland will be 
placed on an aluminum foil boat and then transferred into a Nunc vial, which is capped and immersed into liquid 
nitrogen for snap freezing. 
6.6 Premature Discontinuation of Investigational Agent 
Study treatment will be discontinued for any participant who experiences any of the following:  
• 
Pregnancy 
• 
Any Grade 4 or higher infection 
• 
For AEs associated with laboratory evaluations, any of the following lab abnormalities that persist longer than 5 
days: 
i. 
eGFR < 30 ml/minute/1.73m2 
ii. 
WBC ≤ 1.5 x 109/L 
iii. 
Platelet count < 50 x 109/L 
iv. 
Hemoglobin < 8 g/dL 
v. 
ANC < 1.0 x 109/L 
vi. 
ALT or AST elevation > 5 times ULN 
vii. 
Total bilirubin > 3 times ULN. If Gilbert’s disease, total bilirubin > 3 times baseline value. 
• 
For AEs associated with clinical evaluations, any Grade 3 or higher event as defined by the National Cancer 
Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) that is possibly, or definitely related to 
elotuzumab including anaphylaxis (see Appendix 7: Clinical Criteria for Diagnosing Anaphylaxis)[39] or infusion 
reaction 
• 
Malignancy excluding squamous cell and basal cell carcinoma of the skin 
• 
Disease flare, as defined in Section 3.5.3 
• 
Participants who decide to discontinue the treatment 
• 
The investigator believes that the study treatment is no longer in the best interest of the participant. 
Participants will be expected to remain in the study for follow up despite discontinuation of study drug. Participants who 
discontinue protocol-specified treatment requirements will be treated as medically indicated according to physician 
discretion.   


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7 Concomitant Medications 
7.1 Required Medications 
7.1.1 
Prednisone  
7.1.1.1 
Product Description 
Prednisone tablets will be purchased and over-encapsulated by DAIT NIAID’s Clinical Product Center under 
contract, EMINENT Services Corporation (EMINENT), for the conduct of Protocol AIG01. The over-
encapsulation is for the purpose of patient’s safety and regimen adherence. 
7.1.1.2 
Formulation, Packaging, and Labeling 
EMINENT will over-encapsulate, bottle, label, package and distribute prednisone tablets to the clinical site’s 
investigational pharmacies. The details for the prednisone bottles are as follows: 
DOSE 
Directions 
# of Capsules 
40mg 
1 pill daily for 2 weeks 
30 
30mg 
1 pill daily for 2 weeks 
30 
20mg 
1 pill daily for 1 week 
12 
15mg 
1 pill daily for 1 week 
12 
10mg 
1 pill daily for 1 week 
12 
7.5mg 
1 pill daily for 1 week 
12 
5mg 
1 pill daily for 1 week 
12 
2.5mg 
1 pill daily for 1 week 
12 
 
7.1.1.3 
Dosage and Administration 
Participants in Part 1 and Part 2 will begin dosing with prednisone on the day of their first 
elotuzumab/placebo infusion. The ten-week dosing taper is described below: 
 
Study Day 
Prednisone Dose 
Day 0 to Day 13 
40 mg/day for two weeks, then 
Day 14 to Day 27  
30 mg/day for two weeks, then 
Day 28 to Day 34  
20 mg/day for one week, then 
Day 35 to Day 41  
15 mg/day for one week, then 
Day 42 to Day 48  
10 mg/day for one week, then 
Day 49 to Day 55  
7.5 mg/day for one week, then 
Day 56 to Day 62  
5 mg/day for one week, then 
Day 63 to Day 69  
2.5 mg/day for one week, then 
Discontinue 
 
Based on the investigator’s judgement, participants who present with aggressive disease or who require a 
higher starting dose of prednisone because of a large body mass index may be placed on up to 60 mg 
prednisone daily during the screening period. The dose will need to be decreased to 40 mg prednisone /day 
by the baseline visit. Participants who have been on prednisone 40 mg/day for at least two weeks during 
the screening period will begin Day 0 on 30 mg/day of prednisone and stay on 30 mg/day to Week 4 before 
continuing to taper prednisone from Week 5 onwards according to the schedule described above. 


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Participants on less than 40 mg/day for two weeks during the screening period will begin the prednisone 
taper from Day 0, beginning with 40 mg/day. 
 
It is anticipated that in some participants, an interruption of the protocol-specified prednisone taper may 
be required (e.g., in the setting of an infection). This will be handled as follows: 
 
• 
If the participant’s protocol-specified prednisone taper is modified in the setting of infection, the 
protocol-specified prednisone taper will resume at the dose the participant was taking at the time 
of modification, once medically appropriate.  
7.2 Standard of Care Recommended/Permitted Therapies  
• 
Course of glucocorticoids for non-IgG4-RD indications that are discontinued within 2 weeks: only 2 such courses 
are permitted and must be complete by 8 weeks prior to the Week 48 visit. 
• 
Potential participants are encouraged to obtain vaccines as standard of care per age-specific Center for Disease 
Control and Prevention (CDC) guidelines before participating in the study. Live vaccines must be avoided within 
8 weeks of initiation of study drug. If possible it is suggested participants obtain other immunizations at least 4 
weeks prior to initiation of study therapy. Seasonal flu vaccine should be obtained during the course of the 
study. Other non-live vaccines as needed for standard of care may be administered.  
• 
Concomitant therapies taken for the long term treatment of pre-existing conditions other than IgG4-RD may be 
continued during the study provided they are in accordance with the exclusion criteria and the list of prohibited 
medications. During the study, concomitant medications and new medications should be administered at the 
discretion of the site investigator or treating physician in order to provide the participant with the best possible 
medical care. 
• 
Medications used for prevention and treatment of COVID-19, approved by the FDA or authorized for emergency 
use, are permitted.  
• 
Participants should continue to receive SARS-CoV-2 vaccinations per CDC and FDA recommendations and other 
seasonal vaccinations during the course of the study. 
7.3 Prohibited Medications 
All participants are to have access to any care deemed medically necessary, but administering the following medications, 
for the purposes of this study, are prohibited and will be considered protocol deviations unless administered for a 
disease flare: 
• 
Any systemic glucocorticoids, except for: 
o Prednisone (or equivalent) detailed in Section 7.1.1: Prednisone and in 7.2: Standard of Care 
Recommended/Permitted Therapies 
• 
Any biologic or non-biologic immunomodulating drug therapy including but not limited to methotrexate, 
mycophenolate mofetil, 6-mercaptopurine, tacrolimus, cyclophosphamide, azathioprine, rituximab or other 
CD20 depleting agents.  
• 
Investigational agents or treatments are prohibited during study participation, except for SARS-CoV-2 vaccines 
as specified in Section 6.4.2.3. 
• 
Live vaccines within 8 weeks prior to initiation of study therapy and during study participation.  


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8 Study Procedures 
8.1 Visit Windows  
Appendix 1 presents the Schedule of Events Tables for Part 1 and Part 2. The date for all visits are calculated relative to 
the date of the Baseline/Day 0 Visit.  The visit windows are defined below: 
Part 1A: 
• 
Screening until Baseline/Day 0: 28 days from time of obtaining informed consent until randomization and 
initiation of study treatment 
• 
Weekly infusion visits*: + 3 days / - 1 day 
• 
Every 2-week infusion visits: ± 3 days 
Monthly follow-up visits: ±5 days  
* Weekly infusion visits must be scheduled to allow for a minimum of four full days between infusions. 
 
Part 1B and 2: 
• 
Screening until Baseline/Day 0: 28 days from time of obtaining informed consent until randomization and 
initiation of study treatment 
• 
Day 7: ± 2 days 
• 
Safety Visits (Weeks 4, 12, 20, 28, 36, 44, 48): ± 7 days  
• 
Infusion Visits (Weeks 8, 16, 24, 32, 40): ± 7 days 
8.2 Unscheduled Visits 
Unscheduled visits may be performed if disease activity increases or for other concerns between regularly scheduled 
visits. In the event of a disease flare, the assessments and procedures outlined for the Week 24 visit should be obtained. 
For unscheduled visits conducted for a reason other than a disease flare, participants should be evaluated per clinical 
judgement of the investigator. 
8.3 Screening and Enrollment 
This study will be explained in lay language to each potential participant. Each participant will sign an informed consent 
form before committing to study screening procedures.  
After obtaining informed consent, all screening assessments and procedures to establish eligibility will be performed. 
These may be completed during one or more study visits within the 28-day screening window.  
The following labs, procedures, and assessments will determine participant eligibility: 
8.3.1 
Evaluation of Eligibility and Randomization   
In Part 1, if the participant meets all eligibility criteria for enrollment, then proceed as follows:  
• 
Schedule Baseline/Day 0 Visit (within 28 days of 1st Screening assessment) 
In Part 2, if the participant meets all eligibility criteria for enrollment, then proceed as follows:  
• 
Schedule Baseline/Day 0 Visit (within 28 days of 1st Screening assessment) 
• 
Randomize the participant  
Randomization will be accomplished through a password-protected, web-based, randomization system maintained 
by the Statistical and Clinical Coordinating Center (SCCC). 
 


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8.4 General Assessments  
See Schedule of Events Tables in Appendix 1: Schedule of Visits and Assessments for more detailed information. 
• 
Demographics 
• 
Medical History 
• 
Comprehensive physical examination: to include an evaluation of the head, ears, eyes, nose, throat, lymph 
nodes, heart, lungs, abdomen, skin, extremities, and neurology. 
• 
Targeted physical examination: to include heart, lungs, and abdomen. Additional evaluations to be guided by 
participant complaints and prior abnormalities.  
• 
Vital Signs 
• 
Weight/Height 
• 
Adverse Events  
• 
Concomitant medications: Any medication related to IgG4-RD taken at any point should be recorded. Other non-
IgG4-RD related concomitant medications taken 30 days prior to screening through study completion or 
termination should be reported. 
• 
SARS-CoV-2 Antigen Testing: Participants must be confirmed negative for SARS-CoV-2 by antigen test within 24 
hours of infusion. Participants are provided antigen tests by the site, test themselves, and provide proof of 
negativity. Participants will otherwise will be monitored for SARS-CoV-2 according to institutional standards. 
8.5 Clinical Laboratory Assessments 
• 
Complete Blood Count (CBC) with diff, ANC 
• 
Comprehensive Metabolic Panel: to include total protein, potassium, sodium, calcium, chloride, albumin, 
glucose, blood urea nitrogen (BUN), creatinine, total bilirubin, direct bilirubin, alkaline phosphatase , aspartate 
aminotransferase (AST), alanine aminotransferase (ALT).  
• 
Serum amylase and lipase 
• 
eGFR (calculated centrally based on the Chronic Kidney Disease Epidemiology (CKD-EPI) formula [40]). 
• 
Serum Immunoglobulins 
• 
Serum IgG subclasses 
• 
IgE 
• 
Erythrocyte Sedimentation Rate (ESR) 
• 
C-reactive protein (CRP) 
• 
Serum complement levels: C3 and C4 
• 
TB Testing: IGRA 
• 
Other Infectious Disease Testing: HIV, Hepatitis B surface antigen and core antibody, Hepatitis C antibody test 
• 
Urinalysis: macro, microscopic, culture as indicated 
• 
Serum human chorionic gonadotropin (HCG) (women of child-bearing potential) 
• 
Urine HCG (women of child-bearing potential): pre-infusions 
8.6 Disease-Specific Assessments 
• 
ACR Classification Criteria 
• 
IgG4 History, including all assessments of serum IgG4 concentration obtained within 6 months of the Baseline 
visit. 
• 
CT scan or MRI: chest, abdomen, pelvis. Include head and/or orbits if head/neck/intraocular muscle involvement 
• 
IgG4-RD Responder Index 
• 
Physician Global Assessment VAS 


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• 
Patient Global Assessment VAS 
• 
SF-36 Health Survey 
• 
Flare Assessment 
9 Mechanistic Assays 
During Part 1A, PBMCs and plasma will be isolated and frozen from each participant at baseline and then two days after 
the first elotuzumab infusion. Subsequent samples will also be obtained at 1, 5, 16, 24, and 48 weeks, with 
corresponding clinical blood draws. During Part 1B and 2, samples will be collected at Screening or Baseline/Day 0 and 
Weeks 8, 16, 24, 32, 40 and 48, corresponding with clinical blood draws. Samples should not be collected at Screening if 
the participant is taking glucocorticoids on the day of the Screening Visit. If samples were not collected at the Screening 
Visit, they must be collected at Baseline/Day 0. Mechanistic samples will be obtained on all participants at all sites at the 
specified timepoints. PBMCs and plasma will be stored in liquid nitrogen for preservation. The mechanistic studies will 
be conducted at both the Massachusetts General Hospital/Ragon Institute and Emory University. Further instructions to 
the site on shipment of biospecimen will be provided in the Lab Manual. The following experiments will be carried out in 
batches of 10 participant timepoints per experiment: 
• 
Flow cytometric quantification of plasmablasts, activated B cells, terminally differentiated CD4+CTLs, terminally 
differentiated CD8+CTLs, activated TFH cells, and TPH cells. Terminal differentiation will be defined by the loss of 
CD28 surface expression and gain of CD57 surface expression within the respective effector (CD45RA-CCR7-) T 
cell population. These cell populations will be assessed on the schedule noted above to determine the treatment 
effect on the absolute numbers and proportions of these cell types. 
• 
Quantified cell populations will be analyzed for correlation with one another, disease activity, plasma IgG4 levels 
and clinical responsiveness to elotuzumab. 
• 
From 5 of the enrolled participants with known expansions of the respective cell type and clinical responsiveness 
to elotuzumab, terminally differentiated CD4+CTLs, terminally differentiated CD8+CTLs, and activated B cells will 
be sorted by FACS at weeks 0, 16, 24, and 48. RNA will be isolated to undergo RT-PCR amplification of the TCR-
β/IgH. Next-Generation Sequencing will be used to define the diversity of the TCR/BCR repertoire longitudinally 
to ascertain how elotuzumab may impact clonality. 
9.1 Kinetics of Cell Depletion 
We will determine the kinetics of cell depletion induced by elotuzumab on disease-associated, SLAMF7-expressing 
lymphocyte subpopulations including CD4+ cytotoxic T cells and activated B cells, including plasmablasts.  We will use a 
flow cytometry panel to analyze longitudinal blood samples from participants enrolled in the clinical trial. 
9.2 Mechanistic Assessments 
Mechanistic studies for this trial will include: 
• 
Plasma assays 
• 
PBMC assays 
• 
Single cell RNA sequencing 
• 
Submandibular gland biopsies (MGH participants only) 
9.3 Effect of Elotuzumab at the Tissue Level 
We will determine whether elotuzumab achieves tissue-level depletion of SLAMF7-expressing lymphocyte sub-
populations by examining pre- and post-treatment submandibular gland biopsies by multi-color immunofluorescence to 
quantify infiltrating CD4+CTLs, activated B cells, and plasma cells. 


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During Part 1A, an optional core biopsy of the submandibular gland will be performed at the Baseline visit and again 
between Weeks 16 and 24 to evaluate the tissue response to study therapy. During Part 1B and 2, an optional 
submandibular gland biopsy will be performed prior to the Baseline/Day 0 Visit, following eligibility confirmation, and 
between Weeks 40 and 44. The participants will be instructed to suspend aspirin or NSAID intake 3-7 days before the 
procedure. Core biopsy of the submandibular gland is generally only slightly painful and rarely associated with significant 
morbidity. However, it is possible that a biopsy site might become infected, requiring antibiotic treatment or surgical 
debridement. After application of a topical anesthetic, local anesthetic with vasoconstrictor is infiltrated into the skin 
and subcutaneous tissues external to the submandibular gland. The biopsy is then performed with a large-gauge biopsy 
needle.  The biopsy obtained will be preserved in saline for additional studies. 
We will examine submandibular gland biopsies by multi-color immunofluorescence to quantify infiltrating CD4+CTLs, 
activated B cells, and plasma cells. We hypothesize that elotuzumab will achieve tissue-level depletion of SLAMF7-
expressing lymphocyte subpopulations and this will correspond with clinical improvement. For control salivary gland 
tissue, we will obtain fresh, disease-free margins from the MGH Surgery Department from participants undergoing 
salivary gland resection. Tissue samples will be fixed in formalin, embedded in paraffin and sectioned. Sections will be 
incubated with antibodies specific for CD4, CD8, SLAMF7, TGF-β, GZMA, IFN-γ, CD19, CD27, IgD, CD38, CD138, IgG4 and 
CD57. Lymphocyte subpopulations will be quantified using TissueQuest Software. In addition to demonstrating the 
tissue-level effects of elotuzumab in comparing the pre- and post-treatment samples, the pre-treatment samples will 
also allow accurate quantification of cell-cell interactions by measuring inter-nuclear distances. 
9.4 Determine the Utility of Using the Clonally-expanded Effector Subset (CD57+CD28-) of CD4+CTLs as a Biomarker 
of Disease Activity 
We will determine the utility of using the clonally-expanded effector subset (CD57+CD28-) of CD4+CTLs as a biomarker 
of disease activity by using longitudinally-collected blood samples to quantify these cells by flow cytometry and analyze 
correlations with the IgG4-RD RI. 
9.5 Determine the Utility of Soluble Plasma SLAMF7 Levels as Indicators of Disease Activity 
We will determine the utility of soluble plasma SLAMF7 levels as indicators of disease activity and predictors of disease 
relapse by quantifying soluble SLAMF7 levels in longitudinally-collected plasma samples using sandwich ELISA. 
10 Biospecimen Storage 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the sponsor(s) and their 
agents.  This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participating participants. 
Peripheral blood samples will be obtained for mechanistic studies, as specified in the protocol. Samples will be coded and 
stored at the Ragon Institute of Harvard, MGH, and MIT. The site investigators and site staff are bound to maintain the 
strict confidentiality of medical and research information that may be linked to individuals. 
Additional aliquots will be stored for future studies, which will be guided by results of the investigations planned. See 
Appendix 1: Schedule of Visits and Assessments for detailed schedule and type of samples. 
 
 
 
 
 


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11 Criteria for Participant and Study Completion and Premature Study Termination 
11.1 Participant Completion 
Part 1: All participants will be followed for a total study period of up to 48 weeks, regardless of whether disease flare 
occurs and the participant begins glucocorticoid or alternative immunosuppressive therapy at the Investigator’s 
discretion unless consent has been withdrawn. 
Part 2: All participants will be followed for a total study period of up to 48 weeks, regardless of whether study 
medication has been discontinued as detailed below unless consent has been withdrawn. Completing the Week 48 visit 
is the time point at which the primary outcome is assessed. 
11.2 Participant Withdrawal Criteria 
Participants may be prematurely terminated from the study for the following reasons: 
• 
The participant elects to withdraw consent from all future study activities, including follow-up. 
• 
The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts to reestablish 
contact with the participant have failed).  
• 
The participant dies.  
• 
The Investigator no longer believes participation is in the best interest of the participant. 
• 
The study is stopped by the sponsor.  
11.3 Participant Replacement 
For the primary objective in Part 1 to determine the safety and tolerability of elotuzumab for participants with IgG4-RD, 
participants who prematurely discontinue elotuzumab may be replaced.  Participants who discontinue treatment for 
reasons related to safety or tolerability of the agent will not be replaced.  Participants who discontinue treatment early 
and withdraw from the study without evidence of toxicity or intolerability of the agent will be replaced such that the 
regimen in each cohort will be evaluable in 6 participants.   
For Part 2, participants may be replaced if they withdraw prior to receiving any investigational product.  In this case the 
participant will not count towards the target accrual of 63. 
11.4 Follow-up After Early Study Withdrawal 
Participants wishing to withdraw prematurely from the study will be asked to consent to a final study visit focused on 
collection of safety assessments. 
11.5 Safety Stopping Guidance  
The following events will trigger an ad hoc DSMB review (Section 12.11.3): 
• 
Any death that is at least possibly related to elotuzumab, IgG4-RD, or a study-mandated procedure; 
• 
Any grade 4 adverse event, including infection, that is a clinical event such as a sign/symptom, diagnosis, or 
laboratory abnormality with clinical consequence and at least possibly related to use of the investigational study 
medication. Any life-threatening infusion reactions during infusion of study treatment or within the two-hour 
observation period after study treatment that lead to permanent discontinuation of the infusion, including 
anaphylaxis; 
• 
Two or more of the first 6 treated participants within a given cohort (cohorts 1a, 1b or 2) experience a drug-
related adverse event resulting in the permanent discontinuation of study treatment; subsequently, if >20% of 
participants on study or within a cohort experience a drug-related adverse event resulting in the permanent 
discontinuation of study treatment (as specified in Section 6.6);   


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• 
The occurrence of a Grade 3 or higher related and unexpected SAE in three or more of the study participants 
who have received a study treatment; 
• 
Malignancy; 
• 
Any event which in the opinion of the Protocol Chair or Medical Monitor merits DSMB review. 
 
Events that trigger an ad hoc DSMB review will be cumulative over Parts 1 and 2 of the study. 
12 Safety Monitoring and Reporting 
12.1 Overview 
This section defines the types of safety data that will be collected under this protocol and outlines the procedures for 
appropriately collecting, grading, recording, and reporting those data. Adverse events that are classified as serious 
according to the definition of health authorities must be reported promptly (per Section 12.5) to the IND sponsor, 
DAIT/NIAID.  Appropriate notifications will also be made to site principal investigators (Pis), IRBs, and the U.S. FDA.  
Information in this section complies with ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting, ICH Guideline E-6: Guideline for Good Clinical Practice, 21CFR Parts 312 and 320, and applies 
the standards set forth in the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0: https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
12.2 Definitions 
12.2.1 Adverse Event (AE) 
Any untoward or unfavorable medical occurrence associated with the participant’s participation in the research, 
whether or not considered related to the participant’s participation in the research (modified from the definition of 
adverse events in the 1996 International Conference on Harmonisation E-6 Guidelines for Good Clinical Practice) 
(from OHRP “Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
Adverse Events (1/15/07)” http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2)  
12.2.2 Adverse Reaction and Suspected Adverse Reaction (SAR) 
SAR is any adverse event for which there is a reasonable possibility that the investigational drug caused the adverse 
event. For the purposes of safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug (21 CFR 312.32(a) 
and ICH E2A). 
An adverse reaction (AR) is any adverse event caused by the study drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
12.2.3 Unexpected Adverse Event/Reaction 
A SAR is considered “expected” when it is listed in the investigator brochure, the package insert, or the protocol. A 
SAR is considered “unexpected” when its nature (specificity), severity, or rate of occurrence is not consistent with 
applicable product information as described in the safety information provided in the investigator brochure, the 
package insert, or the protocol (21 CFR 312.32(a) and ICH E2A). A serious unexpected suspected adverse reaction is 
referred to as a SUSAR. For this study, expectedness will be determined by product information provided in the 
investigator brochure, package insert, and protocol for elotuzumab.  


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12.2.4 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or 
sponsor (DAIT/NIAID), it results in any of the following outcomes (21 CFR 312.32(a)): 
1. Death. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either the investigator or 
Sponsor (DAIT/NIAID), its occurrence places the participant at immediate risk of death. It does not include an AE 
or SAR that, had it occurred in a more severe form, might have caused death.  
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 
5. Congenital anomaly or birth defect.  
6. Important medical events that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Elective hospitalizations are not to be reported as an SAE unless hospitalization is prolonged due to complications. 
12.3 Grading and Attribution of Adverse Events 
12.3.1 Grading Criteria 
The study site will grade the severity of adverse events experienced by the study participants according to the criteria 
set forth in the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0. This 
document (referred to herein as the NCI-CTCAE manual) provides a common language to describe levels of severity, 
to analyze and interpret data, and to articulate the clinical significance of all adverse events.  
Adverse events will be graded on a scale from 1 to 5 according to the following standards in the NCI-CTCAE manual: 
Grade 1 = mild adverse event 
Grade 2 = moderate adverse event 
Grade 3 = severe or disabling adverse event  
Grade 4 = life-threatening or urgent intervention 
Grade 5 = death 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, but not limited to, a 
radiograph, an ultrasound, an electrocardiogram etc.), a treatment-emergent adverse event is defined as an increase 
in grade from baseline or from the last post-baseline value that doesn’t meet grading criteria. Changes in grade from 
screening to baseline will also be recorded as adverse events if related to a study-mandated procedure, treatment, or 
change in treatment (but are not treatment-emergent). If a specific event or result from a given clinical or laboratory 
evaluation is not included in the NCI-CTCAE manual, then an abnormal result would be considered an adverse event 
if changes in therapy or monitoring are implemented as a result of the event/result. 
Liver function abnormalities will be graded using alternative criteria which are based on CTCAE version 4.0, and are 
defined relative to the ULN as follows: 
• 
Aspartate aminotransferase [AST] increased 
o Grade 1: > ULN – 3.0x ULN 
o Grade 2: > 3.0x ULN – 5.0x ULN 
o Grade 3: > 5.0x ULN – 20.0x ULN  


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o Grade 4: > 20.0x ULN 
• 
Alanine aminotransferase [ALT] increased 
o Grade 1: > ULN – 3.0x ULN 
o Grade 2: > 3.0x ULN – 5.0x ULN 
o Grade 3: > 5.0x ULN – 20.0x ULN  
o Grade 4: > 20.0x ULN 
• 
Alkaline phosphatase [ALP] increased 
o Grade 1: > ULN – 2.5x ULN 
o Grade 2: > 2.5x ULN – 5.0x ULN 
o Grade 3: > 5.0x ULN – 20.0x ULN  
o Grade 4: > 20.0x ULN 
• 
Blood bilirubin increased  
o Grade 1: > ULN – 1.5x ULN 
o Grade 2: > 1.5x ULN – 3.0x ULN 
o Grade 3: > 3.0x ULN – 10.0x ULN  
o Grade 4: > 10.0x ULN  
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE web site: 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
12.3.2 Attribution Definitions 
The relationship, or attribution, of an adverse event to elotuzumab and prednisone will initially be determined by the 
site investigator and recorded on the appropriate AE electronic case report form (eCRF).  Final determination of 
attribution for safety events that may be eligible for expedited reporting to health authorities will be determined by 
the sponsor, DAIT/NIAID.  The relationship of an adverse event to study therapy regimen will be determined using 
the descriptors and definitions provided in Table 1. In addition, Investigators will report events as possibly related or 
related in situations where the evidence is less than a “reasonable possibility” to suggest a causal relationship 
between elotuzumab and an adverse reaction. AEs whose etiologies may overlap between study product and 
glucocorticoids will be designated as related or possibly related to elotuzumab. 
Table 1. Attribution of Adverse Events 
Code 
Descriptor 
Relationship (to elotuzumab or prednisone) 
UNRELATED CATEGORY 
1 
Not 
Related 
The adverse event is clearly not related; there is 
insufficient evidence to suggest a causal 
relationship. 
RELATED CATEGORIES 
2 
Possible  
The adverse event has a reasonable possibility to 
be related; there is evidence to suggest a causal 
relationship. 
3 
Related 
The adverse event is clearly related. 


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12.4 Collecting and Recording of Adverse Events 
12.4.1 Collection Period 
All adverse events, regardless of severity, should be recorded in the study source documentation and will be 
captured in the database per the following criteria:  
• 
Adverse events of all grades will be collected from the time the participant signs the informed consent until 
he/she initiates study intervention or until he/she is determined to be ineligible to receive study 
intervention, if the investigator determines that the adverse event is related to a study-mandated 
procedure, treatment, or change in concurrent medication.  
• 
Adverse events of all grades will be collected from the initiation of study intervention until completion of the 
study or until 30 days after the participant is prematurely withdrawn (without withdrawal of consent) or 
withdraws from the study, whichever occurs first.  
12.4.2 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing the participant 
• 
Interviewing the participant (e.g., using a checklist, structured questioning, diary, etc.)   
• 
Receiving an unsolicited complaint from the participant 
• 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an adverse 
event, as defined in Section 12.3, Grading and Attribution of Adverse Events 
12.4.3 Recording Adverse Events 
Throughout the study, the investigator will record adverse events and serious adverse events as described previously 
(Section 12.2, Definitions) on the appropriate eCRF regardless of the relationship to study therapy regimen or study 
procedure. Events will be recorded on the appropriate AE case report form (CRF) for this study. 
Once recorded, an AE will be followed until it resolves with or without sequelae, or until the end of study 
participation, or until 30 days after the participant prematurely withdraws (without withdrawing consent)/or is 
withdrawn from the study, whichever occurs first. 
An SAE will be followed until it resolves with or without sequelae OR until 30 days after the end of study participation 
if consent has not been withdrawn.  
If the AE is related to a laboratory or diagnostic evaluation, the evaluation that produced the value or result should 
be repeated until that value or result returns to normal or can be explained and the participant’s safety is not at risk. 
12.5 Reporting Adverse Events and Serious Adverse Events to Sponsor: DAIT/NIAID 
12.5.1 Reporting Adverse Events 
This section describes the responsibilities of site investigators to report adverse events to the study sponsor 
(DAIT/NIAID) via the SCCC. Timely reporting of all adverse events is required.  
Unless otherwise noted below in Section 12.5.2 for serious adverse events and events requiring reporting within 24 
hours, AEs must be recorded on the AE eCRF within five (5) days of discovery of the event. Whenever possible, a 
diagnosis should be provided, rather than compilation of signs/symptoms, with grade of the event dictated by 
highest grade of the sign/symptom component. 


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12.5.2 Reporting of Serious Adverse Events 
This section describes the responsibilities of the site investigator to report serious adverse events and events that 
need to be reported within 24 hours to the sponsor via the eCRF. Timely reporting of adverse events is required by 21 
CFR Part 312.32 and ICH E6 guidelines.  
The adverse events outlined below must be reported by the site investigators to DAIT/NIAID via the SCCC regardless 
of relationship or expectedness to study intervention within 24 hours of occurrence/discovery, whichever occurs 
first: 
• 
All SAEs per 21 CFR 312.32 definitions (see Section 12.2.4, Serious Adverse Events). 
• 
In addition, the following events need to be reported within 24 hours:  
o Any lab abnormalities that persist longer than 5 days leading to study drug discontinuation (see Section 
6.6). 
o Grade 3 or higher infusion reaction. 
o Anaphylaxis, defined as a serious allergic reaction that is rapid in onset and may cause death (see 
Appendix 7: Clinical Criteria for Diagnosing Anaphylaxis)[39]. 
o Grade 3 or greater infection. 
o All disease flares as defined in Section 3.5.3.  
• 
All other Clinical events with a NCI-CTCAE Grade 3 or greater severity deemed possibly or definitely related to 
elotuzumab. 
Note: clinical events include signs/symptoms, diagnoses, and laboratory abnormalities with clinical consequence 
(defined as the requirement for intervention, correction, increased monitoring, or further evaluation). 
When a site investigator identifies a serious adverse event or event specified as a 24 hour reportable event above, he 
or she must notify DAIT/NIAID via the SCCC within 24 hours. Site investigators are to report these events on the SAE 
eCRF in Electronic Data Capture (EDC). Sites are encouraged to download a blank SAE eCRF in the beginning of the 
study in an event EDC becomes unavailable/ inaccessible, the site investigator should complete the paper SAE form 
and email to Rho_productsafety@rhoworld.com.  However, within the next business day or when the EDC system 
becomes functional, the SAE eCRF must be completed. 
All requested information on the SAE eCRF should be provided. Unavailable details of the event at time of initial 
report should not delay submission of known information. The initial report should include at a minimum: AE term, 
relationship to study intervention (i.e., elotuzumab, prednisone), and reason why event is serious (per definitions) or 
requires 24 hour reporting. Supplementary CRF pages including medical history, concomitant medications, 
demographics, study drug administration, and death must be provided. As additional details become available, the 
SAE eCRF should be updated and submitted. With each iteration of the form, the investigator (or designated sub-
investigator) must sign the form electronically. 
For additional information regarding SAE reporting, contact Rho Product Safety (SCCC):  


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12.6 Reporting to Health Authorities 
After an adverse event requiring 24 hour reporting (per Section 12.5.2, Reporting of Serious Adverse Events) is 
submitted by the site investigator and assessed by DAIT/NIAID, there are two options for DAIT/NIAID to report the 
adverse event to the appropriate health authorities (Annual Reporting and Expedited Reporting). 
12.6.1 Annual Reporting 
DAIT/NIAID will include in the annual study report to health authorities all adverse events classified as: 
• 
Serious, expected, suspected adverse reactions (see Section 12.2.2, Adverse Reaction and Suspected Adverse 
Reaction, and Section 12.2.3, Unexpected Adverse Event/Reaction). 
• 
Serious and not a suspected adverse reaction (see Section 12.2.2, Adverse Reaction and Suspected Adverse 
Reaction). 
• 
Pregnancies. 
Note that all adverse events (not just those requiring 24-hour reporting) will be reported in the Annual IND Report. 
12.6.2 Expedited Safety Reporting  
This option applies if the adverse event is classified as one of the following: 
• 
Serious and unexpected suspected adverse reaction [SUSAR]: 
o A single occurrence of an event that is uncommon and known to be strongly associated with drug 
exposure 
o One or more occurrences of an event that is not commonly associated with drug exposure, but is 
otherwise uncommon in the population exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical control group 
The sponsor (DAIT/NIAID) will notify the appropriate health authorities (FDA) and all participating investigators of 
Expedited Safety Reports within 15 calendar days; unexpected fatal or immediately life-threatening suspected 
adverse reaction(s) will be reported as soon as possible or within 7 calendar days.  
Final Study Report: A complete summary of safety information (including both Standard and Expedited reports as 
defined above) is included in the final study report to be submitted to the US FDA at the closure of the protocol. 
12.7 Reporting of Adverse Events to IRBs/IECs 
All investigators shall report AEs and SAEs, including IND safety reports, in a timely fashion to the IRB in accordance with 
applicable regulations and guidelines.  
12.8 Reporting Pregnancy 
The investigator shall be informed immediately if a female study participant becomes pregnant, or if a male participant 
becomes aware of a pregnancy in a female partner anytime during the year period of participation. A pregnant 
participant shall be instructed to stop taking study medication. The investigator shall counsel the participant and discuss 
the risks of continuing with the pregnancy and the possible effects on the fetus. Monitoring of the pregnant participant 
shall continue until the conclusion of the pregnancy.   
The investigator shall report to the sponsor (DAIT/NIAID) via the SCCC all pregnancies that occur in female study 
participants within 24 hours of becoming aware of the event according to the procedures specified in Section 12.5.2. The 
Pregnancy eCRF will be used to submit the information for tracking purposes only, as the pregnancy itself is not 


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considered an AE or SAE.  All female participant pregnancies identified during the study shall be followed to conclusion 
and the outcome of each must be reported.  The Pregnancy information must be updated and submitted to the SCCC via 
the eCRF form as new information becomes available.  
Information requested about the delivery shall include: 
• 
Gestational age at delivery 
• 
Birth weight, length, and head circumference 
• 
Gender 
• 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 minutes, and 24 hours after 
birth, if available 
• 
Any abnormalities 
All pregnancy complications that result in a congenital abnormality, birth defect, miscarriage, and medically indicated 
abortion should be submitted on the SAE eCRF form.  
The investigator shall also report to DAIT/NIAID all male participant partner pregnancy outcomes by eCRF when this 
information can be obtained. Specific information collected will include number of infants; gender, weight, length, and 
head circumference of each infant; any infant complications, medical problems, or congenital anomalies. Informed 
consent will be pursued from the pregnant partner to obtain this information for the database. 
12.9 Reporting Unanticipated Problems 
An investigator must promptly notify the sponsor (DAIT/NIAID) via the SCCC if an “unanticipated problem involving risks 
to participants or others” is identified, which is not otherwise reportable as an adverse event. 
12.10 Review of Safety Information 
12.10.1 Medical Monitor Review 
The DAIT/NIAID Medical Monitor shall receive monthly reports from the SCCC compiling new and accumulating 
information on AEs, SAEs, and pregnancies recorded by the study site(s) on appropriate eCRFs. 
In addition, the Medical Monitor shall review and make decisions on the disposition of the SAE and pregnancy 
reports received from the SCCC. 
12.11 Data Safety and Monitoring Board Review  
12.11.1 Routine DSMB Reviews  
The progress of the study will be monitored by the NIAID DSMB. The NIAID Autoimmune DSMB will be chartered to 
review safety data and to make recommendations to NIAID regarding continuation, termination, or modification of 
the study.  The DSMB will review the safety data approximately 6 months after the first participant is treated.   
Following the initial review, the DSMB will review the safety data twice annually during planned DSMB Data Review 
Meetings. Data for the planned safety reviews will include, at a minimum, a listing of all reported AEs and SAEs as 
well as an evaluation for a safety signal by arm by the DAIT Statistical and Coordinating Center.  
The DSMB chair will be informed of any IND Safety Reports in a timely manner in order to make a recommendation 
for an ad hoc full board review and /or protocol suspension. Discontinuation of study treatment will also be 
periodically reported to the DSMB. In addition, safety data will be reviewed by the DSMB when an event occurs that 


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is of sufficient concern to the NIAID medical monitor or protocol co-chairs to warrant review, or when an event 
occurs that could contribute to a stopping rule.  
12.11.2 Protocol-Defined Interim Safety Reviews 
Interim safety reviews will be undertaken by a SRC comprised of a subgroup of the DSMB. The study design (Section 
3.1) specifies an interim safety analysis and review by the SRC of the first dosing cohort occur one month after the 
last participant enrolled has completed dosing and the week 9 visit has occurred as described in Section 13.5.2. 
Recommendation to continue by the SRC is required, with enrollment of the second dosing cohort (every 2 months) 
as specified per Protocol Section 3.1.1.  A second interim safety analysis and review by the SRC will take place after 
the last participant in the Part 1B, twelve-month dosing cohort has completed  dosing and the week 48 visit has 
occurred.  
Following the protocol-specified safety review between dosing cohorts, the SRC can recommend actions regarding 
study conduct, including, but not limited to, the following: 
1. Continue the study as planned. 
2. Add participants to an existing dosing cohort. 
3. Reduce the number of weeks of study drug administration for the next higher dosing cohort. 
4. Stop the study. 
 
Recommendation by the SRC is required in order to begin enrollment in Part 2. Unless the safety data suggests 
otherwise the twelve-month dosing regimen will be used in Part 2.  
12.11.3 Ad hoc DSMB Reviews  
If any of the events listed in Safety Stopping Guidance, Section 11.5 occur, the chair of the DSMB will be notified and 
a review of the safety data will be performed.  The DSMB will have the discretion to recommend actions regarding 
study conduct, and will determine if enrollment in the study should be stopped and/or administration of 
investigational study medication should be halted.  
If any of the first 2 events occur, then no new participants will be consented, and no new participants will be 
enrolled, until after the DSMB completes review of the safety data. Participants in the screening phase of the study 
may continue to undergo minimal risk procedures. 
If any of the remaining events occur, the study will proceed as planned pending DSMB review of the data. However, if 
two weeks has elapsed and the DSMB has not met, then no new participants will be consented, and no new 
participants will be enrolled, until after the DSMB completes review of the safety data.  
In the event that a temporary halt is placed on consent and enrollment, participants already enrolled in the study will 
continue to receive study medication if they are not the participant of the DSMB review. 
13 Statistical Considerations and Analytical Plan 
13.1 Overview  
This is a two-part multi-center clinical trial in participants with active IgG4-RD.  Part 1 is an open-label phase to 
determine the safety and tolerability of elotuzumab and to select the duration of treatment for evaluating efficacy of the 
agent. Part 2 is a randomized, placebo-controlled, double-blinded phase to compare the efficacy of the addition of 


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elotuzumab versus placebo to prednisone in participants with IgG4-RD. The primary efficacy endpoint is disease 
response. 
13.2 Endpoints 
Primary, secondary, and exploratory endpoints are listed in Sections 3.2, 3.3, and 3.4. 
13.3 Measures to Minimize Bias  
In Part 2, randomization to treatment allocation will be performed to minimize bias in the comparison of the primary 
and secondary efficacy endpoints.  Randomization will be stratified by newly-diagnosed or relapsing disease at entry to 
minimize confounding with the effects of treatment.  In addition, the use of a placebo-controlled design for elotuzumab 
will minimize the risk of ascertainment bias in the IgG4-RD Responder Index and assessments of efficacy and safety 
endpoints in Part 2 of the study. 
13.4 Analysis Plan 
13.4.1 Analysis Populations 
In Part 1:  
Safety population: will be defined for each treatment regimen as all participants who received any amount of 
investigational product. 
In Part 2: 
Modified Intent-to-Treat (mITT) population: will be defined as all participants who undergo random assignment and 
receive any amount of elotuzumab / elotuzumab-placebo. The primary efficacy analyses will be based on the mITT 
population according to the groups to which the participants are assigned. 
Per Protocol (PP) population: will be defined as the subgroup of participants in the mITT population who (1) receive 
at least 5 of 6 elotuzumab / elotuzumab-placebo infusions or discontinue treatment due to a disease flare  (2) receive 
at least 80% and no more than 120% of the cumulative dose of prednisone during the 10 week taper defined in 
Section 7.1.1.3, (3) adhere to the permitted single course of glucocorticoids for non-IgG4-RD indications defined in 
Section 7.2 and (4) have no major protocol deviations or ineligible entry criteria that would impact efficacy 
assessments through week 48. 
A masked data review will evaluate deviations from the protocol in a blinded manner for impact on the efficacy 
assessments and exclusion from the PP population.  This may include, but is not limited to, violations of entry criteria, 
departures from assigned treatment regimen, modifications of concurrent therapy, failure to complete study visits, or 
administration of study procedures outside the specified visit windows. 
Safety population: will be defined as all participants who received any amount of at least one elotuzumab / 
elotuzumab-placebo infusion. Safety analyses will be based on the actual treatment which the participants receive. 
13.4.2 Primary Analysis of Primary Endpoint  
Part 1 
Descriptive statistics will be used to summarize the proportion of participants in each cohort who experience at least 
one Grade 3 or greater adverse event during study participation for all participants in the safety population. The 
primary analysis of efficacy and safety endpoints will be conducted after all participants in Cohort 1a and 1b complete 
the Week 48 assessments or are withdrawn from the study. 


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Part 2 
The primary endpoint for Part 2 is disease response at 48 weeks, defined as the percent improvement in the IgG4-RD 
RI score over baseline: 
% 끫歸끫歸끫歸끫歸끫歸끫歸끫歸끫歸끫歸끫歸끫歸 끫殬끫歸 끫歸끫歸끫歸4끫殊끫殊 끫殊끫歸끫殔끫殔끫殔끫殔 48 = 100 ∗(끫歸끫歸끫歸4끫殊끫殊끫殊끫歸끫歪끫歪끫歪끫殔끫歪끫歪끫歪끫殔−끫歸끫歸끫歸4끫殊끫殊끫殊끫歸끫殔끫殔끫殔끫殔 48
끫歸끫歸끫歸4끫殊끫殊끫殊끫歸끫歪끫歪끫歪끫殔끫歪끫歪끫歪끫殔
 ) 
For participants whose IgG4-RD RI score is worse (e.g. higher) at week 48 than baseline, their % Improvement in IgG4-
RD RIWeek 48 will be considered 0%. Additionally, participants who use glucocorticoids or other immunosuppressants 
beyond that permitted by protocol, or who experience a disease flare as defined in Section 3.5.3 at any time point 
before 48 weeks will be defined as achieving no disease response (0%). 
The observed levels of disease response at 48 weeks will be summarized by arm in the mITT population as the 
median, interquartile range, and range.  A between-group comparison of the assessment of disease response at 48 
weeks will be performed using a Wilcoxon-Mann-Whitney test with a two-sided Type I α of 0.05, and will be reported 
with a two-sided 95% confidence interval for the Mann-Whitney parameter (Section 13.6) derived under the 
proportional odds assumption [41]. The primary analysis of disease response will treat all participants who drop out 
of the study prior to reaching week 48 for any reason, including a disease flare, initiation of non-protocol therapy, or 
any other reason to cause them to be unevaluable using the IgG4 Responder Index, as having no disease response 
(0% improvement) for the primary endpoint. The primary analysis will be conducted after all participants in Cohort 2 
complete the Week 48 assessments or are withdrawn from the study.  
13.4.3 Supportive Analyses of the Primary Endpoint  
A supportive analysis of the primary endpoint will consider participants who drop out of the study prior to reaching 
week 48 without evidence of disease flare, initiation of non-protocol therapy, or other indications of increased 
disease activity as missing-completely-at-random (MCAR). Descriptive statistics and the Wilcoxon-Mann-Whitney test 
will be repeated in the subgroup of the mITT population excluding participants with data MCAR.  A masked data 
review panel will evaluate participant disposition and all disease activity assessments in a blinded manner to define 
the types of missing data. In addition, analysis of the primary endpoint will be repeated as a van Elteren test with a 
covariate for the stratification factor of newly-diagnosed versus relapsing disease at study entry.  As an additional 
supportive analysis which does not assume data are MCAR, a two-dimensional tipping point analysis of missing data 
will be conducted.  Additional details on supportive analysis will be specified in the Statistical Analysis Plan. 
Supportive analyses of the primary endpoint will be repeated in the PP populations and as a preplanned subgroup 
analysis in participants who are identified as having elevated serum IgG4 level prior to initiation of study therapy.  
The subgroup is defined as any serum IgG4 concentration greater than 1.5 times the upper limit of normal that is 
obtained within 6 months of the Baseline visit or at the baseline assessment of Serum IgG subclasses.  
 
13.4.4 Analyses of Secondary and Other Endpoints 
The key secondary endpoint for Part 2 is complete response at 48 weeks, defined as an IgG4-RD RI Score of 0 and a 
glucocorticoid dose of 0 mg/day and no flare since beginning treatment.  A fixed sequence testing procedure will be 
conducted with the primary efficacy endpoint, to control the overall Type I error rate at 0.05.  Specifically, if the 
between-group comparison of disease response at 48 weeks reaches statistical significance, a comparison of the 
rates of complete remission at 48 weeks will be performed using a Fisher’s Exact test with a two-sided Type I α of 
0.05. If the between-group comparison of disease response at 48 weeks fails to reach statistical significance, 


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inferences on complete remission will be supportive without overall Type I error control.  The proportion in complete 
remission in each arm will be reported with two-sided 95% Clopper-Pearson confidence intervals. All participants in 
the mITT population who drop out of the study prior to reaching week 48 for any reason, including a disease flare, 
initiation of non-protocol therapy, or any other reason to cause them to be unevaluable using the IgG4 Responder 
Index, will be defined as not achieving complete remission. 
All inferential analyses for the additional secondary efficacy endpoints are considered supportive; p-values for test of 
differences among groups will be presented without adjustment for multiple comparisons. All secondary endpoints 
will be analyzed in the mITT and PP populations, and in the subgroup with elevated serum IgG4 level prior to 
initiation of study therapy. 
For all dichotomous efficacy endpoints, Fisher’s Exact tests will be conducted and two-sided 95% Clopper-Pearson 
confidence intervals will be reported.   
Frequency counts of the number of disease flares and the number of organ sites with disease-related damage will be 
reported by arm, and between-group comparison will be performed using Fisher’s Exact Test. 
For secondary continuous efficacy endpoints, including the Physician Global Assessment and Patient Global 
Assessment, descriptive statistics will be used to summarize the distribution of scores in each arm.  The absolute 
change from baseline will be analyzed using an analysis of covariance model (ANCOVA) with treatment allocation as 
the independent variable.  
Treatment group differences for the safety endpoints will be compared using a Fisher’s exact test. 
13.4.5 Descriptive Analyses  
Summary statistics for baseline and demographic characteristics, disposition, and medication use will be provided for 
the mITT and PP populations. These data will be presented in the following manner: 
• 
Continuous data (e.g. age, weight, and height) will be summarized by mean, standard deviation, median, and 
range. 
• 
Categorical data (e.g. sex and race) will be presented as counts and percentages. 
All medications taken by or administered to study participants beginning 30 days before the Screening Visit and 
continuing throughout the study will be collected. All medications used will be coded according to the World Health 
Organization (WHO) drug dictionary. The number and percentage of participants receiving prior and concomitant 
medications/therapies will be presented overall and by medication class. 
13.5 Interim Analyses  
13.5.1 Interim Analysis of Efficacy Data 
No early stopping for increased efficacy of the addition of elotuzumab versus placebo to prednisone is planned for 
this study. 
13.5.2 Interim Analysis of Safety Data 
In Part 1, an interim analysis of safety will be conducted as described in Sections 3.1.1, 3.1.2 and 12.11.2.  To make a 
determination on the safety of proceeding to Cohort 1b in Part 1 and proceeding to Part 2, the SRC will perform a 
broad review of all of the safety data in an independent and unbiased fashion. Safety analysis reports to be provided 


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for review will include tables, listings and figures, including the following within each dosing group using the safety 
population: 
• 
AE summary tables will report the number of events and the number and percentage of participants having at 
least one event in the following categories: 
o All AEs (overall and classified by MedDRA system organ class and preferred term) 
o AEs indicated as serious  
o AEs with an outcome of death 
o AEs by severity 
o AEs that lead to study drug discontinuation 
o AEs by relatedness to each study drug 
• 
Clinical laboratory measurements will be summarized and plotted over time, including: 
o Complete Blood Count with differential/ANC 
o Comprehensive Metabolic Panel: total protein, potassium, sodium, calcium, chloride, albumin, glucose, 
blood urea nitrogen (BUN), creatinine, total bilirubin, direct bilirubin, alkaline phosphatase, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT). 
o Serum amylase and lipase 
o eGFR 
o Serum Immunoglobulins 
o Erythrocyte Sedimentation Rate (ESR) 
o C-reactive protein (CRP) 
o Serum complement levels: C3 and C4 
• 
All disease flares as defined in Section 3.5.3 
• 
Vital Signs, physical examinations, use of medications, and other observations related to safety 
Full details on the content and generation of safety reports will be specified in the Statistical Analysis Plan. 
In Part 2, no formal interim analysis of safety data is planned for this study. Routine reviews by the NIAID 
Autoimmune Data and Safety Board will be conducted as defined in Section 12.11.   
13.5.3 Futility Analysis 
No early stopping for futility is planned for this study. 
13.6 Statistical Hypotheses  
In Part 2, the null hypothesis for the Wilcoxon-Mann-Whitney test is defined according to the Mann-Whitney parameter 
[42], as the probability that a randomly selected individual in the treatment arm will have a better outcome than a 
randomly selected individual in the control arm, with an adjustment for ties [43]. Specifically, let 끫殖끫歰 be a random 
outcome from a population to receive elotuzumab, and 끫殖끫殆 be a random outcome from a population to receive placebo. 
Then,    
끫歶0: 끫毾= 끫殆끫歸(끫殖끫歰> 끫殖끫殆) + 1 2
ൗ∙끫殆끫歸(끫殖끫歰= 끫殖끫殆) = 0.5 
The alternative hypothesis is that there is unequal probability that the addition of elotuzumab treatment is superior to 
the addition of placebo in achieving disease response at 48 weeks.     
끫歶1: 끫毾=  끫殆끫歸(끫殖끫歰> 끫殖끫殆) + 1 2
ൗ∙끫殆끫歸(끫殖끫歰= 끫殖끫殆) ≠0.5 
 


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13.7 Sample Size Considerations  
In Part 1, no formal power analyses were conducted and all safety and tolerability evaluations are considered 
exploratory. The target sample size for this part of the study is 12 participants with at least 6 participants receiving 
elotuzumab under each treatment regimen. The ability to detect significant events of certain frequencies was 
considered. Table A illustrates the probability of observing at least 1 significant event in a dosing cohort of 6 
participants. 
Table A Probability of Observing at Last One Event 
 
True Probability of Event 
 
0.1 
0.2 
0.3 
Probability of observing at least 1 event in 6 
participants 
0.47 
0.74 
0.88 
 
Additionally, Table B displays the upper and lower limits of the exact 95% Clopper-Pearson confidence interval for a 
binary outcome. 
Table B Confidence Limits for a Binary Outcome 
Number with 
an event 
Proportion 
with event 
Lower Limit 
for Exact 95% 
CI 
Upper Limit 
for Exact 95% 
CI 
0 
0.000 
0.000 
0.459 
1 
0.167 
0.004 
0.641 
2 
0.333 
0.043 
0.777 
3 
0.500 
0.118 
0.882 
4 
0.667 
0.223 
0.957 
5 
0.833 
0.359 
0.996 
6 
1.000 
0.541 
1.000 
   
In Part 2, a 2:1 allocation ratio was selected to evaluate aspects of treatment, including both safety of the combination 
of elotuzumab with prednisone and the exploratory objectives of the study. The sample size for Part 2 was determined 
by specifying the natural parameter to the Wilcoxon-Mann-Whitney test of  끫毾= 0.75 would warrant further 
investigation of the agent.  The probability of 0.75 was selected as a target effect size for this proof-of-concept study 
using a simulation study based on the scale of the IgG4 RI and variable rates of improvement and achievement of 
complete remission. Under Gaussian assumptions, the Mann-Whitney parameter is equivalent to a mean difference of 
1.0 standardized units. Using the formula from Noether [44], and with the desired allocation ratio of 2:1 to receive 
elotuzumab versus placebo in addition to the prednisone-taper, N = 63 participants (nE = 42, nP = 21) would provide 90% 
power to detect the target effect-size.  For the secondary efficacy endpoint of  complete remission at 48 weeks, Yunyun 
et al. [8] reported a complete remission rate at 6 months of approximately 25% with glucocorticoid treatment alone.  
With the target sample size of 63 participants, a Fisher exact test using α = 0.05 (two-sided) will have at least at 80% 
power (exact power = 0.826) to detect an improvement from 25% to 65% in the complete remission rate at 48 weeks 
with the addition of elotuzumab.    
 


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14 Identification and Access to Source Data 
14.1 Source Data 
Source documents and source data are considered to be the original documentation where participant information, 
visits consultations, examinations and other information are recorded.  Documentation of source data is necessary for 
the reconstruction, evaluation and validation of clinical findings, observations and other activities during a clinical trial.  
14.2 Access to Source Data 
The site investigators and site staff will make all source data available to the DAIT/NIAID, NIAID representatives, agents, 
employees, contractors, and other persons assisting in conducting, monitoring, or analyzing the study, as well as to 
relevant health authorities, and Bristol-Myers Squibb Company.  Authorized representatives as noted above are bound 
to maintain the strict confidentiality of medical and research information that may be linked to identified individuals. 
15 Quality Assurance and Quality Control 
The principal investigator is required to keep accurate records to ensure that the conduct of the study is fully 
documented. The principal investigator is required to ensure that all eCRFs are completed for every participant entered 
in the trial. The period of record retention should be consistent with the record retention policies of the sponsoring 
agency or applicable regulatory agencies. However, in certain instances, documents should be retained for a longer 
period if required by the applicable regulatory agency or by the National Institutes of Health. 
Data will be obtained from a variety of sources including, but not limited to laboratory notebooks, automated 
instrument output files, and clinical participant charts. Data from these source materials will be transmitted to the DAIT 
data center via one of two mechanisms. Data collected electronically at central laboratories will be transferred 
electronically directly from the laboratory to the DAIT data center using standard secure data transfer procedures. Data 
collected at the clinical sites will be transmitted to the DAIT data center using an internet-based remote data entry 
system. Clinical site personnel use an internet browser to key data into eCRFs; each CRF page is submitted to the clinical 
database electronically as the page is completed. Univariate data validation tests are performed as the data are keyed. 
The clinical database is backed up nightly; backup tapes are saved in a secure, off-site location. At any time, authorized 
site personnel may log in to the remote data entry system, review and correct previously entered data, or key additional 
data. The data will be further validated per the study data validation plan via a series of computerized and manual edit 
checks, and all relevant data queries will be raised and resolved on an ongoing basis. Complete, clean data will be frozen 
to prevent further inadvertent modifications. All discrepancies will be reviewed and any resulting queries will be 
resolved with the investigators and amended in the database. All elements of data entry (i.e., time, date, verbatim text, 
and the person performing the data entry) will be recorded in an electronic audit trail to allow all data changes in the 
database to be monitored and maintained in accordance with federal regulations.   
Monitors are responsible for regular inspection of the conduct of the trial, for verifying adherence to the protocol, and 
for confirming the completeness, consistency, and accuracy of all documented data.  
Monitors will periodically visit the participating clinical sites and audit the source documents in order to validate the 
data in the central database. Data will be provided using the participant’s screening or enrollment number, the DAIT 
data center will not collect personally identifying information such as the participant’s name or social security number. 
Participants will provide demographic information such as race, ethnicity, and birth date. 


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Data collected by the DAIT data center will be held in the strictest confidence, and are protected from access that could 
reveal personally identifying information about any participant in the trial. 
16 Protocol Deviations 
16.1 Protocol Deviation Definitions 
Protocol Deviation –  Any change, divergence, or departure from the study design or procedures constitutes a protocol 
deviation.  Protocol deviations occur for a variety of reasons, such as an investigator’s intentional or unintentional 
departure from the protocol, the participant’s lack of adherence to the protocol, or external/environmental factors (e.g., 
severe weather or holidays) that change the performance of a protocol. Some protocol deviations are anticipated 
and/or intentional; others are not. Some protocol deviations are known or identified before they occur; others are only 
discovered to have occurred after the fact. The investigators and site staff will conduct the study in accordance to the 
protocol; no deviations from the protocol are permitted or approved beforehand by the study Sponsor. 
Major Protocol Deviation (Protocol Violation) – A Protocol Violation is a deviation from the IRB approved protocol that 
may affect the participant’s rights, safety, or well-being and/or the completeness, accuracy and reliability of the study 
data.  In addition, protocol violations include willful or knowing breaches of human subject protection regulations, or 
policies, any action that is inconsistent with the NIH Human Research Protection Program’s research, medical, and 
ethical principles, and a serious or continuing noncompliance with federal, state, local or institutional human subject 
protection regulations, policies, or procedures. 
Non-Major Protocol Deviation – A non-major protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that does not have a major impact on the participant’s rights, safety or well-
being, or the completeness, accuracy and reliability of the study data. 
16.2 Reporting and Managing Protocol Deviations 
The study site principal investigator has the responsibility to identify, document and report protocol deviations as 
directed by the study Sponsor.  However, protocol deviations may also be identified during site monitoring visits or 
during other forms of study conduct review.  
When a deviation occurs, corrective actions may be necessary depending on the nature of the deviation. Risk 
assessment must occur by the PI and study Sponsor. The PI should ensure a procedure for the timely correction and 
documentation of problems identified by study personnel, outside monitors or auditors, or other parties involved in the 
conduct of a study. The depth of Corrective Action/Preventive Action (CAPA) required should match the risk and impact 
on safety of participants and/or the quality of the data. 
Upon determination that a protocol deviation has occurred, the PI/designated study staff will report the deviation 
according to the processes outlined for the study. A major deviation is to be reported within 3 business days and 
reported by the PI to the IRB per IRB reporting requirements.  The study Sponsor will determine reportability of the 
deviation to the DSMB and FDA as applicable.   
17 Ethical Considerations and Compliance with Good Clinical Practice 
17.1 Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for Industry: E6 Good 
Clinical Practice Consolidated Guidance, and according to the criteria specified in this study protocol.  Before study 


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initiation, the protocol and the informed consent documents will be reviewed and approved by an Institutional Review 
Board.  Any amendments to the protocol or to the consent materials will also be approved by the IRB before they are 
implemented. 
17.2 Informed Consent Process 
The consent process will provide information about the study to a prospective participant and will allow adequate time 
for review and discussion prior to his/her decision.  The principal investigator or designee listed on the FDA 1572 will 
review the consent and answer questions.  The prospective participant will be told that being in the trial is voluntary and 
that he or she may withdraw from the study at any time, for any reason.  All participants (or their legally acceptable 
representative) will read, sign, and date a consent form before undergoing any study procedures.  Consent materials will 
be presented in participants’ primary language. A copy of the signed consent form will be given to the participant. 
The consent process will be ongoing. The consent form will be revised when important new safety information is 
available, the protocol is amended, and/or new information becomes available that may affect participation in the 
study.  
17.3 Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant will be assigned a 
unique identification number and these numbers rather than names will be used to collect, store, and report participant 
information.  Site personnel will not transmit documents containing personal health identifiers (PHI) to the study 
sponsor or their representatives. 
The study protocol, documentation, data and all other information generated will be held in strict confidence.  No 
information concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor. 
The study Monitor or other authorized representatives of the sponsor may inspect all documents and records required 
to be maintained by the Investigator, including but not limited to, medical records (office, clinic or hospital) and 
pharmacy records for the participants in this study.  The clinical study sites will permit access to such records. 
18 Publication Policy 
The Autoimmunity Centers of Excellence (ACE) publication policy will apply to publication of study results. Authorized 
study personnel may find details regarding the policy on the ACE study portal. Site investigators are encouraged to 
communicate and publish study results with prior notification of and review by DAIT, NIAID, and Bristol-Myers Squibb.  


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Gut, 2010. 59(9): p. 1245-51. 


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26. 
Abignano, G., et al., The enhanced liver fibrosis test: a clinical grade, validated serum test, biomarker of overall 
fibrosis in systemic sclerosis. Ann Rheum Dis, 2014. 73(2): p. 420-7. 
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Brennan, A.J., et al., Protection from endogenous perforin: glycans and the C terminus regulate exocytic 
trafficking in cytotoxic lymphocytes. Immunity, 2011. 34(6): p. 879-92. 
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Chang, H.F., et al., Endocytosis of Cytotoxic Granules Is Essential for Multiple Killing of Target Cells by T 
Lymphocytes. J Immunol, 2016. 197(6): p. 2473-84. 
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Lee, J.K., et al., CS1 (CRACC, CD319) induces proliferation and autocrine cytokine expression on human B 
lymphocytes. J Immunol, 2007. 179(7): p. 4672-8. 
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Wallace, Z.S., et al., The 2019 American College of Rheumatology/European League Against Rheumatism 
Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol, 2020. 72(1): p. 7-19. 
31. 
Wallace, Z.S., et al., The 2019 American College of Rheumatology/European League Against Rheumatism 
classification criteria for IgG4-related disease. Ann Rheum Dis, 2020. 79(1): p. 77-87. 
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Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis 
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363(3): p. 221-32. 
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Stone, J., et al., Final results of an open label phase 2 study of a reversible B cell inhibitor, Xmab® 5871. IgG4-
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Erickson, L., et al., Short-circuiting long-lived humoral immunity by the heightened engagement of CD40. J Clin 
Invest, 2002. 109: p. 613-620. 
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assessment. Conf Proc IEEE Eng Med Biol Soc, 2009. 2009: p. 6554-6. 
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Hofmeister, J.K., Cooney, D., and Coggeshall, K.M., Clustered CD20 induced apoptosis: src-family kinase, the 
proximal regulator of tyrosine phosphorylation, calcium influx, and caspase 3-dependent apoptosis. Blood Cells, 
Molecules, and Diseases, 2000. 26(2): p. 133-143. 
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Deans, J.R., et al., Rapid redistribution of CD20 to a low density detergent-insoluble membrane compartment. 
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39. 
Sampson, H.A., et al., Second symposium on the definition and management of anaphylaxis: summary report--
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J 
Allergy Clin Immunol, 2006. 117(2): p. 391-7. 
40. 
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Fay, M.P. and Y. Malinovsky, Confidence intervals of the Mann-Whitney parameter that are compatible with the 
Wilcoxon-Mann-Whitney test. Statistics in medicine, 2018. 37(27): p. 3991-4006. 
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Fay, M.P., et al., Causal estimands and confidence intervals associated with Wilcoxon-Mann-Whitney tests in 
randomized experiments. Statistics in medicine, 2018. 37(20): p. 2923-2937. 
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16 The IgG4-RD RI will need to be repeated at Baseline/Day 0 if there has been a change in Prednisone or other DMARD or if there has been an apparent change in disease activity between Screening 
and Baseline. 
17 Participants must be confirmed negative for SARS-CoV-2 by antigen test within 24 hours of infusion. Participants are provided antigen tests by the site, test themselves, and provide proof of 
negativity. 
18 Mechanistic assessments should not be collected at screening if the participant is taking glucocorticoids on the day of the Screening Visit. If Mechanistic Assessments were not collected at the 
Screening Visit, they must be collected at Baseline/Day 0. 
19 Submandibular gland biopsy can be completed during the screening period once eligibility has been confirmed. 
    
 
   




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20.2.1 Immunostaining for ACR/EULAR Classification 
 
 
 
 
 
 




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20.6 Appendix 6: SF-36 Health Survey 
 
 


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20.7 Appendix 7: Clinical Criteria for Diagnosing Anaphylaxis 
 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or                              
both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, 
incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to 
several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP* 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline 
PEF, Peak expiratory flow; BP, blood pressure. 
* Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg + [2 x age]) from 1 to 10 years, and 
less than 90 mm Hg from 11 to 17 years. 
Adapted from the Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network [39] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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20.8 Appendix 8: Acceptable Contraception Methods for Females of Reproductive Potential 
 
Acceptable Contraception Methods for Females of Reproductive Potential* 
Option 1 
Methods to Use Alone 
• 
Intrauterine devices (IUDs) 
• 
Tubal sterilization 
• 
Patient’s partner had a vasectomy 
• 
Implant 
OR 
Option 2 
Choose One Hormone 
Method AND One 
Barrier Method 
Hormone Methods 
choose 1 
 
Barrier Methods 
choose 1 
Estrogen and Progesterone 
• 
Oral contraceptive pill 
• 
Transdermal patch 
• 
Vaginal ring 
• 
Injection  
 
AND 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Contraceptive sponge 
• 
Male condom 
• 
Female condom 
OR 
Option 3 
 
Choose One Barrier 
Method from each 
column (must chose 
two methods) 
Barrier Methods 
choose 1 
 
Barrier Methods 
choose 1 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Contraceptive sponge 
 
AND 
• 
Male condom 
• 
Female condom 
 
* Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not 
passed through menopause.  
 
Adapted from the Mycophenolate REMS (Risk Evaluation and Mitigation Strategy): https://www.mycophenolaterems.com/