Clinical trial NCT02954159
Conditions: Ulcerative Colitis
Sponsor: Medical College of Wisconsin
Start date: 2017-05-18; Completion date: 2019-01-31
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to assess if a combination therapy of tacrolimus and vedolizumab is superior to vedolizumab monotherapy for induction of remission in moderate to severe UC, and its effect on long and short-term outcomes including colectomy rate. Secondary aim of this study is to assess the safety of tacrolimus as an induction agent in patients with UC.

Detailed description:
Phase III studies have shown that patients with UC who received vedolizumab had a higher rate of clinical response, clinical remission and mucosal healing when compared to placebo3. Nevertheless, while clinical response rate was almost 50%, the rate of clinical remission at 6 weeks was only 16.9. In comparison, in the ACT trials almost 40% of patients achieved remission at week 84. The delayed onset of action of vedolizumab monotherapy in patients with UC may lead to a higher colectomy rate and limit the use of vedolizumab in patients with active disease who require rapid induction of remission. Corticosteroids are used as a bridging agent to rapidly induce remission. However, steroid refractory or dependent disease and steroid intolerance are common. Furthermore, steroids have devastating side effects.

Tacrolimus inhibits the complexion of calcineurin with its respective cytoplasmic receptors cyclophilin and FK-binding protein 12 (FKBP-12), both of which regulate a calmodulin dependent-phosphatase. Tacrolimus has been found to be efficacious in the treatment of patients with moderate to severe UC. Unfortunately, because of the safety profile with long term use, the drug is mostly used as an induction agent.

While switching to vedolizumab from another drug that has not been efficacious or has lost effectiveness (or starting vedolizumab as a first agent) can be beneficious in the long term, patients need an induction agent in order to achieve remission in a short period of time. Tacrolimus is a widely used drug to prevent implant rejection after a transplant. Randomized controlled trials have shown that is highly effective with good response rates even after 2 weeks of therapy. In order to avoid side effects, tacrolimus is usually used for a limited amount of time (12-14 weeks), which is sufficient time to induce remission of disease. Unfortunately, as other inflammatory bowel diseases, UC recurs and patients also require a maintenance therapy. While tacrolimus has been used with good results as a long term agent, the ideal scenario is to avoid its long term use as there is still a potential for side effects and a need for a very strict close monitoring. This is why a long term maintenance agent is needed to keep the patient in remission. Until recently, no ideal agent was available for this purpose, as while anti-tumor necrosis factor agents (infliximab and adalimumab) have been approved for ulcerative colitis, its combination with another agent that induces systemic immunosuppression (in this case, tacrolimus) could potentially increase the risk of infections and/or malignancies. Because vedolizumab is gut selective, does not affect the entire immune system and post-marketing studies have confirmed its safety profile. This makes it a perfect combination agent to tacrolimus, theoretically decreasing the potential side effect while increasing its efficacy.

The hypothesis is that the addition of tacrolimus as an induction agent to a standard regimen of vedolizumab increases the efficacy of the drug, decreasing the rate of need for colectomy and other complications while quickly improving the patients' quality of life without significantly increasing the risk of adverse events.

Arms: arm 1: vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) arm 2: vedolizumab at standard regimen with placebo.
Interventions: intervention 1: Tacrolimus intervention 2: Vedolizumab intervention 3: Placebo
Intervention descriptions: intervention 1: Oral tacrolimus tablet starting at 0.05mg/kg twice daily, with dose adjustments aiming for serum trough levels of 10-15 ng/ml during the first 2 weeks, and 5-10ng/ml subsequently. intervention 2: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. intervention 3: Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm.

Protocol documents:
ICF_000.pdf: 
Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
Page 1 of 18 
Version:  
 
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Medical College of Wisconsin and Froedtert Hospital 
INTRODUCTION TO THE INFORMED CONSENT 
 
Name of Subject: ____________________________ 
 
Induction of Remission and Response of Vedolizumab Monotherapy Vs. Combination Therapy 
with Tacrolimus in Patients with Moderately to Severely Active Ulcerative Colitis 
 
Andres Yarur, MD 
Department of Medicine / Gastroenterology 
414-955-6729 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee WI 53226 
 
 
You are invited to take part in this research. You can decide whether to take part in this project 
or not. You are free to say yes or no. If there is anything that you do not understand, please ask 
questions. 
 
 
Definitions 
Ulcerative Colitis – a type of chronic inflammatory bowel disease (IBD) 
characterized by inflammation, deterioration/narrowing of the intestinal wall, and/or the 
presence of ulcers in the colon. Some common symptoms are stool urgency, abdominal 
pain, blood in the stool, and constipation.  
Vedolizumab – a drug used for the management and treatment of inflammatory bowel disease 
(Entyvio) 
Tacrolimus – a drug used for suppressing the immune system in patients that have had organ 
transplants (Prograf). It is not approved by the FDA for the treatment of IBD.  
Standard of Care – Routine care; care you would receive to treat your IBD regardless of study 
participation.  
Flexible Sigmoidoscopy – an examination that looks at the inside of the lower or sigmoid portion of 
the colon (large intestine) and rectum 
 
Biopsy – tissue samples, about the size of a pencil tip, snipped from the bowel during the 
sigmoidoscopy procedure.  


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
Page 2 of 18 
Version:  
 
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Purpose 
This project is being done to find out whether 
a new combination of drugs for ulcerative 
colitis, vedolizumab with tacrolimus, is better 
than vedolizumab alone.  
Length 
▪ You will be in this research project for 
about 32 weeks.  
 
Risks 
This is a brief list of the most commonly seen 
side effects. The full consent form after this 
introduction contains a more complete list of 
potential research risks. 
 
Drug risks: 
▪ 
Kidney injury 
▪ 
Tremor 
▪ 
Infection 
 
Flexible Sigmoidoscopy risks: 
▪ 
Heavy or ongoing bleeding from 
biopsy, pain, bloating, perforation, 
nausea, vomiting, irritation 
 
Procedures 
 
List of visits: 
▪ 
Screening 
- Total Number: 1 
- Total Time: up to 8 hours 
▪ 
Baseline Visit 
- Total Number: 1 
- Total Time: 2 hours 
▪ 
Weeks 2,6,8,14 
- Total Number: 4 
- Total Time: 1.5 hours 
 
▪ 
Lab visits (blood draws)/phone calls 
- Total Number: up to 36 
- Total Time: varies 
 
▪ 
Week 30 phone call 
- Total Number: 1 
- Total Time: 20 minutes 
 
Procedures that will occur at various 
visits: 
 
Invasive Procedures 
- During screening and at week 6, you 
will have a flexible sigmoidoscopy. 
At each visit, and sometimes 
between visits, you will have your 
blood drawn for labs.  
 
Non-invasive Procedures 
- You will be asked to provide a stool 
sample 3 times.  
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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Version:  
 
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My Other Options 
You do not have to join this project. Your other 
options may include: 
▪ Joining a different project 
▪ Routine care for this condition  
▪ Getting no treatment for this condition 
 
Benefits 
We don’t know if this project will help you. Your 
condition may get better but it could stay the 
same or even get worse. 
If you have more questions about this project at any time, you can call Dr. Yarur at 414-955-
6858 
 
If you have questions about your rights as a participant, want to report any problems or 
complaints, or offer input, you can call the MCW/Froedtert Hospital Research Subject 
Advocate at 414-955-8844. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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CONSENT TO PARTICIPATE IN RESEARCH 
A1. INTRODUCTION – WHY ARE WE ASKING YOU TO PARTICIPATE? 
You are being invited to participate in this research because you have moderate to severe 
ulcerative colitis and are starting vedolizumab as part of your clinical care. Because of your 
condition, you may be eligible for a research project on a new drug for ulcerative colitis, to be 
used with your vedolizumab.  
 
A total of about 20 people are expected to participate in this research, all at the Medical College 
of Wisconsin/Froedtert Hospital. 
 
The Director of the project is Dr. Andres Yarur in the Department of Medicine / 
Gastroenterology. A research team works with Dr. Yarur. You can ask who these people are.  
 
Takeda, a drug company, is funding the research.  
 
A2. DO I HAVE TO PARTICIPATE? 
You can decide whether to take part in this research or not. You are free to say yes or no. If you 
say no, your regular medical care will not change. Even if you join this project, you do not have 
to stay in it. You may stop at any time.  
 
A research project is different from routine medical care in three ways: 1) there are extra risks 
that we will tell you about in this form; 2) you may have some extra medical tests and visits; 3) 
the research procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS PROJECT BEING DONE? 
In this study we want to find out whether a new combination of drugs for ulcerative 
colitis, vedolizumab with tacrolimus, is better than vedolizumab alone. Vedolizumab is 
an FDA-approved treatment for ulcerative colitis. To do this, we will compare the two 
treatments in people with ulcerative colitis and see which one reduces symptoms faster 
or better, and which one is safer (causes fewer problems). Tacrolimus is approved by 
the U.S. Food and Drug Administration for use in patients, but not for treating patients 
with ulcerative colitis. The combination of vedolizumab with tacrolimus may have 
advantages over vedolizumab alone, but we won’t know until we do more research. 
 
We don’t know if this study will help you. Your condition may get better but it could stay 
the same or even get worse. We hope the information from this study will help us 
develop a better treatment for ulcerative colitis in the future. 
 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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B1. WHAT WILL HAPPEN IF I PARTICIPATE?  
At the end of this form, a table is attached. This table is the schedule of study procedures. 
Procedures that are done only for the study (research only) are highlighted. The other 
procedures are part of your standard of care or information pulled from your medical record.  
 
Screening procedures:  
If you decide to join the study, some screening tests will be done first to see if you are 
eligible. 
• 
You will be asked to sign this informed consent 
• 
You will have a flexible sigmoidoscopy to determine the severity of your disease. Part of 
this procedure will include a biopsy for the lab to rule out an infection called CMV. 
A flexible sigmoidoscopy is an examination that looks at the inside of the lower or sigmoid 
portion of the colon (large intestine) and rectum. The examination uses a tool called a 
colonoscope or flexible sigmoidoscope. On the day of the examination you may be given 
medicine prior to the examination to help you relax; you could have some discomfort during the 
examination. You will lie on your left side with your knees drawn up toward your chest. The 
colonoscope or flexible sigmoidoscope is inserted into the anus and, under visual control, is 
gently moved into the rectum and through the sigmoid colon. Air will be inserted through the 
scope to provide a better view and suction may be used to remove fluid or stool. You may feel 
pressure as the scope moves inside. Following the examination, you will be kept in an 
observation area for an hour or so until the effects of the medications (if administered) that have 
been given adequately wear off. Passing gas is necessary and should be expected. Feeling 
bloated and swollen are also common due to the air inflated into the bowel; this usually lasts 
only 30 to 60 minutes. You must plan to have someone take you home after the test, because 
you will be drowsy and unable to drive in the event sedating medication was administered. 
During the examination the study doctor looks at the lining of the bowel and snips tissue 
samples, called biopsies from the bowel for further study, to make sure you don’t have an 
infection called CMV. Each biopsy is about the size of a pencil-tip.  
• 
We will review some information from your medical record – results of recent 
colonoscopy/sigmoidoscopy, labs, medications, and medical history relating to 
your ulcerative colitis 
• 
A urine pregnancy test will be performed if you are a woman of child bearing 
potential. 
If the screening information shows that you meet the requirements, then you will be able 
to start the study. If the screening information shows that you cannot be in the research 
study, the study doctors will discuss other options with you and/or refer you back to your 
regular doctor. 
 
Research groups  
To find out if vedolizumab with tacrolimus treats ulcerative colitis more effectively than 
vedolizumab alone, one group of people in the study will be given vedolizumab and 
tacrolimus, and a second group of people will be given vedolizumab and a placebo. 
 
You should know that the placebo is a pill that contains no real medicine and we do not 
expect it will do anything for your health. 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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Because no one knows which of the treatments is best, you will be randomized into one 
of the two study groups. One group will receive vedolizumab and tacrolimus, and one 
group will receive vedolizumab and a placebo. Randomization means that you are put 
into a group by chance. It is like flipping a coin. You will have an equal chance of being 
placed in either group. 
 
Since the expectations of patients and doctors can influence the results of a study, 
neither you nor your study doctor can know which drug you will get until the study is 
over. This is called a blinded study. A computer program chooses which group you are 
in, and the pills in each group will look the same. In an emergency, your doctor can find 
out which drug you are taking. 
 
Summary of Procedures: 
Baseline assessment 
• 
collect information from your routine care appointment, including vital signs, lab 
results, and scores for assessing the severity of your symptoms. 
• 
begin study medication 
• 
laboratory tests (phosphorus, magnesium, tacrolimus level) 
A stool sample is needed to measure fecal calprotectin. - these are 
not part of your routine care and are considered research only 
Weeks 2 and 8 - this visit is not part of your routine care and is considered research only 
• 
vital signs (blood pressure, heart rate, temperature, weight) 
• 
we will ask you about medications you are taking 
• 
we will ask you about side effects you may be having 
• 
laboratory tests (complete blood count [CBC], comprehensive metabolic panel, 
phosphorus and magnesium levels, tacrolimus level (these tests will require the 
collection of about 30 ml (2 tablespoons) of blood), pregnancy testing (at week 2 only) 
• 
you will be asked to complete questionnaires/scores for assessing the severity of 
your symptoms 
Weeks 6 and 14 – these visits are part of your routine care, and only noted laboratory tests are 
considered to be for the study only 
• 
vital signs (blood pressure, heart rate, temperature, weight) 
• 
we will ask you about medications you are taking 
• 
we will ask you about adverse events (side effects) you may be having 
• 
flexible sigmoidoscopy (week 6 only) 
• 
laboratory tests (CBC, CMP, CRP) 
• 
tacrolimus, phosphorus, and magnesium levels, and a stool sample 
for fecal calprotectin – these are not part of your routine care and are considered 
research only 
• 
pregnancy testing – this is not part of your routine care and is considered 
research only 
• 
you will be asked to complete questionnaires/scores for assessing the severity of 
your symptoms 
Weekly Phone Call 
• 
The study coordinator will call you weekly for the first 14 weeks of the study to 
assess for side effects or concerns. At Week 12, your call will also include a reminder to 
stop your study medication.  
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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Week 30 
• 
review of your medical record 
• 
phone call to ask you about your health and check for adverse events 
 
You will also be asked to record your daily symptoms (stool frequency and rectal 
bleeding) in a diary for the 12 weeks that you are receiving the study drugs. This diary 
will be shared with the research team. 
 
You will receive intravenous vedolizumab at Weeks 0 (baseline visit), 2, and 6, and 
every 8 weeks thereafter. This is part of your standard of care.  
 
Tacrolimus (or placebo) will be started on the same day as your first vedolizumab dose. 
The tacrolimus/placebo is a tablet that you will take daily at home. The dose of the 
tacrolimus may be adjusted to make sure you are getting the appropriate amount. 
These adjustments will be made based on the levels of tacrolimus measured in your 
blood. Adjustments may be made even if you are in the control group and receiving the 
placebo just to make sure that neither you nor your doctor can figure out which group 
you have been assigned to. 
 
B2. HOW LONG WILL I BE IN THE PROJECT? 
You will be in this research study for about 32 weeks – 30 weeks enrolled in the study, plus 
about 2 weeks to complete screening procedures. You will take the study drug for 12 weeks.   
 
B3. CAN I STOP BEING IN THE PROJECT?   
You are free to withdraw from the project at any time. If you leave, your regular medical care will 
not change. If you are thinking about leaving, please tell the research doctor.  
• 
The research doctor can tell you about the effects of stopping, and you and the 
research doctor can talk about what follow-up care would help you the most. 
• 
You might be asked to come back for one more visit to check your health. 
• 
You might be asked to return your research drug containers. 
 
The research doctor may take you out of this project at any time. This would happen if: 
• 
They think it is in your best interest. 
• 
You do not follow the project rules. 
• 
The whole project is stopped. 
If this happens, the research doctor will tell you. 
 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE PROJECT?  
You should not eat or drink grapefruit products or take medications called CYP3A inducers or 
CYP3A inhibitors while on study medication. A list of these medications will be provided to you.  
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE PROJECT? 
There are risks to taking part in any research project. There is a risk that you may get a drug 
combination that does not help your condition or may make it worse.  There also may be 
problems (side effects) we do not know about yet, from the drug itself, or how it combines with 
other drugs you are taking. If we learn about new important side effects, we will tell you.  
 
We watch everyone in the project for problems (side effects). You need to tell the research 
doctor or a member of the research team immediately if you experience any problems, 
side effects, or changes in your health.   
 
 
C2. RISKS OF TACROLIMUS 
The research drug itself may cause problems (side effects).  Side effects may be mild or very 
serious.  Some can last a long time or never go away. Many go away soon after you stop taking 
the drug. Drugs can affect individuals in different ways.  
 
The side effects that other people have experienced so far with the tacrolimus are: 
• 
Kidney injury: patients may develop a rise in serum creatinine (a marker of kidney 
function), which is usually reversible when decreasing or discontinuing the 
drug. Chronic kidney damage is rarely seen in patients on short courses of 
therapy. 
• 
Hypertension: tacrolimus may raise the blood pressure. 
• 
Neurological side effects: Tremors are a common side effects of tacrolimus, and 
are usually temporary, even without dose adjustment. Rarely, patients may 
develop headaches. Studies have shown mild tremors in up to 20% of patients 
and headaches in about 5%. Seizures were previously reported, but they are 
usually seen with intravenous administration of the drug and patients with 
previous history of seizures will be excluded from the study. 
• 
Metabolic abnormalities: Tacrolimus may cause high blood sugar, but no severe 
cases have been reported. 
• 
Rare side effects: loss of appetite, nausea, vomiting, diarrhea, and abdominal 
discomfort. Increased liver enzymes are reversible with dose reduction or drug 
discontinuation. 
• 
Infections: there is a theoretical risk of infections in patients on 
immunosuppressants. Tacrolimus may predispose the patients to infection with 
pneumocystis jiroveci, a rare type of pneumonia or lung infection. 
 
C3. OTHER RISKS OF THIS RESEARCH PROJECT  
Other procedures and medications that are part of the research also involve some risks: 
• 
Vedolizumab - Most common adverse reactions: nose, mouth, and throat 
irritation; headache; joint aches; nausea; fever; upper respiratory tract infection; 
fatigue; cough; bronchitis; influenza; back pain; rash; itching; sinusitis; and pain 
in extremities. 
• 
PML - Both vedolizumab and tacrolimus have warnings in the label for the risk of 
a rare infection of the brain, called progressive multifocal leukoencephalopathy 


Medical College of Wisconsin & Froedtert Hospital 
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Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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(PML). There have been some potential reports of PML associated with 
immunosuppressant drugs including tacrolimus. There is also a potential risk with 
vedolizumab, although to date, no cases have been reported that are directly attributed 
to vedolizumab. Patients will be monitored for any new onset, or worsening, of 
neurological signs and symptoms, including the typical signs and symptoms associated 
with PML that are diverse, progress over days to weeks, and include progressive 
weakness on one side of the body or clumsiness of limbs, disturbance of vision, and 
changes in thinking, memory, and orientation leading to confusion and personality 
changes. Since the progression of deficits usually leads to death or severe disability over 
weeks or 
months, the study drug(s) will be stopped immediately if PML is suspected, and 
the patient will be referred to a neurologist. 
• 
Vaccines - You should not receive live vaccines while you are taking tacrolimus. 
The people you live with should also not receive live vaccines. If you or someone 
you live with needs a vaccine during the course of a study, please talk to a member of 
the study team. 
• 
Interactions with other medications, herbals, and food - Foods (such as grapefruit 
juice) and medications, including herbal remedies can change the way your body 
processes the study drugs. A member of the study team will talk to you about your 
current medications and you should tell someone on the study team before you start any 
new medications during the study. 
• 
Blood draw – The side effects you might experience from giving a blood sample 
for this study include possible discomfort and bruising at the needle entry site. Rare 
complications from any venipuncture (drawing blood from a vein) include fainting, arterial 
puncture, nerve injury, infection, and blood clot. Precautions will be taken to ensure your 
safety and minimize discomfort. The person drawing your blood will observe you for side 
effects. 
• 
Flexible sigmoidoscopy – discomforts and risks associated with a sigmoidoscopy include 
: Heavy or ongoing bleeding from biopsy or removal of polyp; cramping, pain, and 
abdominal bloating; Peritonitis (inflammation of the lining of the abdominal cavity); 
Perforation (a hole) of the intestinal wall. Surgery may be needed if a perforation occurs; 
Nausea, vomiting, bloating, or rectal irritation caused by the bowel cleanse prep; 
medication side effects, like drowsiness following sedative or pain medication if given; or 
an allergy to the anesthesia. 
• 
Biopsy – biopsy risks include : persistent bleeding at the site of the biopsy; pain; 
infection. Biopsy results can identify abnormalities and even cancer of the intestine you 
did not know about.  
  
C4. REPRODUCTIVE RISKS 
Risks to women who could become pregnant  
The drug in this project might affect a baby, before or after the baby is born. We do not know if 
the drug causes harm to a baby, so we do not want anyone who might be pregnant to enter the 
project. You should not become pregnant or nurse a baby while in this project. You must tell the 
research doctor right away if you think you are pregnant. You will be asked to have a pregnancy 
test to be sure you are not pregnant at the start of the project and periodically during the study.   
 
You may not donate eggs during your participation in the project.  


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
Page 10 of 18 
Version:  
 
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If you become pregnant during the project, you will be dropped from participation for safety 
reasons. If you become pregnant while you are taking this experimental drug, we ask that you 
inform the research doctor immediately. The research doctor will ask you for written permission 
to obtain information from you or your obstetrician on your pregnancy and the health of the 
baby. 
 
Risks of fathering a child 
You should not father a baby while taking part in this project because it is unknown if the drug 
could affect a baby. If your partner is able to become pregnant, one or both of you must use 
some form of effective birth control.  You must tell the research doctor right away if you think 
your partner is pregnant. 
Birth control methods for all subjects 
Check with the research doctor about the birth control methods needed for this project and how 
long to use them. Some methods might not be good enough for this project. If you are having 
sex that could lead to pregnancy, you should use birth control while you are in this project.   
This may include: 
• 
Not having vaginal sex (abstinence) 
• 
Taking birth control pills orally 
• 
Having birth control shots or patches such as Depo-Provera 
• 
Surgical sterilization (hysterectomy or tubal ligation) 
• 
Use of an intrauterine device (IUD) 
• 
Use of diaphragm with contraceptive jelly 
• 
Use of condoms with contraceptive foam 
• 
Use of diaphragm with condoms (“double barrier”) 
• 
Limiting sexual activity to a male partner who has had a vasectomy 
If you are not surgically sterile or abstinent, you should use 2 methods of contraception. You 
should continue using birth control for 4 weeks after stopping the study drug.  
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE PROJECT? 
We don’t know if this study will help you. Your condition may get better but it could stay the 
same or even get worse. We hope the information from this study will help us develop better 
treatments for ulcerative colitis.  
 
D1. ARE THERE ANY COSTS TO BEING IN THE PROJECT? 
Most of the medical care that you will receive in this study is considered routine care for 
your condition and would be recommended whether you join the study or not. Costs for 
routine care will be billed to you or your insurance carrier. 
Activities / costs that are part of the study will not be billed to you or your insurance 
company. These are: 
• 
Flexible sigmoidoscopy / biopsy 
• 
Urine pregnancy test 
• 
Tacrolimus level 
• 
Magnesium level 
• 
Phosphorus level 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
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IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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• 
Tacrolimus or placebo 
• 
Magnesium (if needed) 
• 
Phosphorus 
• 
CBC 
• 
Comprehensive metabolic panel done at times other than screening, week 6, and week 
14 
• 
Fecal calprotectin 
 
Some insurers will not pay for drugs, tests or hospitalization that are part of research 
studies, so check with your insurer before you join this study. If you have questions 
regarding study costs, please contact Dr. Yarur. 
If you participate in this research, the costs of any necessary emergency medical treatment in 
the event of a research-related injury will be billed to you or your health insurance. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE PROJECT? 
You will receive $250 for each week you are in the study, for 14 weeks. This totals $3500. This 
is to compensate you for time spent on study visits and lab draws, including mileage / travel. If 
you do not complete 14 weeks of the study, your payments will be prorated by week. To pay 
you, we need your social security number. Any payment may be reportable as income on your 
taxes. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this project. You are free to say yes or no. If you do not join this project, 
your research doctor can discuss other healthcare choices with you.  
Your other choices may include: 
• 
Not participating in any research and continuing your routine care 
• 
Joining a different research project 
• 
The procedure or drug offered to you may also be available without being in any 
research project. 
 
The research doctor can explain both the possible benefits and the risks of other options that 
are available to you. 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE PROJECT? 
If we learn any important new information about the drugs that might change your mind about 
being in the project, we will tell you about it right away.  You can then decide if you want to stay 
in the project. 
 
Clinically relevant results, including individual results, will be disclosed to you, when the study is 
done.  
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
Page 12 of 18 
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D5. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE PROJECT?  
Emergency medical treatment for injuries directly related to your participation in this research 
project will be provided to you. You or your health insurance will be billed for the costs of this 
emergency treatment.  MCW will decide on a case by case basis if they will reimburse you or 
your insurer for emergency treatment costs.  If your research-related injury requires medical 
care beyond this emergency treatment, you or your insurer will be responsible for the costs of 
this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this project, contact 
the research doctors right away.  Contact information: 414-805-7128 (study team)  
 
Nothing in this consent form affects any legal rights you may have nor does it release the 
investigator, the sponsor, the institution, or its agents from liability for negligence. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE PROJECT? 
• 
If you have more questions about this project at any time, you can call Dr. Yarur at 414-
805-6858. 
• 
If you have questions about your rights as a research participant, want to report any 
problems or complaints, or offer input, you can call the MCW/Froedtert Hospital Research 
Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this project? 
To be in this research project, the research team needs your permission to access, collect and 
use some of your health information. If you say no, you cannot be in the project. This 
information may come from questions we ask, forms we ask you to fill out, or your medical 
record, as described below. We will only collect and use information needed for the project. 
 
The protected health information (PHI) originates from services you will or have received at one 
or more of the following locations: the Medical College of Wisconsin (MCW); BloodCenter of 
Wisconsin (BCW); Children’s Hospital of Wisconsin (CHW); any Froedtert Health Affiliate- 
Froedtert Memorial Lutheran Hospital (FMLH), Inc.; Community Memorial Hospital (CMH) 
Menomonee Falls, Inc.;  St. Joseph’s Community Hospital (SJH) West Bend, Inc.;  Froedtert & 
The Medical College of Wisconsin Community Physicians Clinics, Inc. (FMCWCP); the West 
Bend Surgery Center, LLC; and the Froedtert Surgery Center, LLC.  
 
The health information to be collected and used for this project is:  
 Your medical record as it relates to your ulcerative colitis treatment and diagnosis 
 Your medical record relating to your care in this study 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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E2. Who will see the health information collected for this project? 
The only MCW/Froedtert Hospital employees allowed to handle your health information are 
those on the research team, those on the Institutional Review Board (IRB) and those who check 
on the research activities to make sure the hospital’s rules are followed. 
 
If the costs of any necessary emergency medical treatment in the event of a research-related 
injury are billed to your health insurance, your health information may need to be disclosed to 
the insurer for billing purposes. 
 
Because this project involves the use of drugs and/or devices, the FDA also has the right to 
inspect all project records. 
 
We may record your research information, including results of tests and procedures done for 
research, in your Froedtert Hospital and/or Medical College of Wisconsin medical record.  As a 
result, this research information may be seen by people allowed to see your medical records for 
healthcare operations or treatment, by those you allow to see your medical records by giving 
written permission, and by others when required by law. 
 
We will not use your personal health information for a different project without your permission 
or the permission of a hospital research review board (IRB). Once all personal identification is 
removed from your health information the information may be used for future research or 
distributed to another investigator for future research without additional informed consent from 
you or your legally authorized representative. The information might also be used or released 
for other purposes without asking you. Results of the project may be presented in public talks or 
written articles, but no information will be presented that identifies you. 
  
E3. What are the risks of sharing this health information? 
One risk of taking part in a research project is that more people will handle your personal health 
information collected for this project. The research team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. 
Depending on the kind of information being collected, it might be used in a way that could 
embarrass you or affect your ability to get insurance. If you have questions, you can talk to the 
research doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this project? 
If you sign this form, we plan to keep your information for 10 years after the research project 
ends, for paper data collected, and indefinitely for electronic data, in case we need to check it 
again for this project. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health information, you 
need to send a letter to Dr. Yarur at Medical College of Wisconsin, Division Gastroenterology 
and Hepatology, 8701 Watertown Plank Road, Milwaukee WI 53226. The letter must say that 
you have changed your mind and do not want the researcher to collect and share your health 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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information. At that time, we may decide that you cannot continue to be part of the project. We 
may still use the information we have already collected.  
 
E6. Access to records 
If you join this project, you will be given one of two treatments without knowing exactly which 
one (a “blinded” project). If you ask to see your health records during this “blinded” project, the 
research team cannot tell you which drug you are being given. This is because the research 
team also remains “blinded” about which drug the sponsor has randomly assigned to you. You 
would have to wait until the time given below. We cannot do the project unless you agree. 
However, if the blinded information is needed to treat you, it will be provided to the research 
doctor. 
• 
What are the blinded options? You will get one of these drugs/interventions: Vedolizumab 
and Tacrolimus or Vedolizumab alone 
• 
When can you find out which drug you were given? You can find out 30 weeks after you 
start the study.  
 
F1. FOR MORE INFORMATION ABOUT THE PROJECT 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
You can look up this project by referring to the ClinicalTrials.gov number NCT02954159 or by 
asking the research team for a printed copy.    
 
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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CONSENT TO PARTICIPATE 
 
By signing my name below, I confirm the following: 
• 
I have read (or had read to me) this entire consent document, including Attachment 1.  
All of my questions have been answered to my satisfaction. 
• 
The project’s purpose, procedures, risks and possible benefits have been explained to me.   
• 
I agree to let the research team use and share the health information and other information 
gathered for this project. 
• 
I voluntarily agree to participate in this research project. I agree to follow the procedures as 
directed. I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please keep it 
where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date   OR 
Date/Time 
 
 
 
Name of Witness (if applicable) 
please print  (for short form consent 
process, or consent of blind or 
illiterate subject) 
Signature of Witness 
 
Date 
 
 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date 
 
 
 
 
Name of Principal Investigator         
please print  
__ I participated in consent process 
__ I acknowledge enrollment of this 
subject into the project 
Signature of Principal 
Investigator 
Date 
 
 
Attachment 1 – Details of project schedule and procedures 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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Schedule of Events 
 
Schedule of 
events 
Pre-
treatment 
 
 
Treatment 
Follow 
Up 
Screening 
Week 
0 
Week 
2 
Week 
6 
Week 
8 
 Week 
12 
Week 
14 
When 
needed
1 
Week 
30 
Informed 
Consent 
✔ 
 
 
 
 
 
 
 
 
Begin tacrolimus 
 
✔ 
 
 
 
 
 
 
 
Begin 
vedolizumab 
 
✔ 
 
 
 
 
 
 
 
Stop tacrolimus 
 
 
 
 
 
✔ 
 
 
 
Prior 
medications 
✔ 
 
 
 
 
 
 
 
 
Concomitant 
medications 
 
✔ 
 
 
✔ 
✔ 
✔ 
 
✔ 
 
✔ 
Demographics 
✔ 
 
 
 
 
 
 
 
 
Smoking status 
✔ 
 
 
 
 
 
✔ 
 
 
Medical/surgical 
history 
✔ 
 
 
 
 
 
 
 
 
Vitals signs  
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔2 
Body mass (Kgs) 
✔ 
✔ 
 
 
 
 
 
 
 
Urine pregnancy 
test (women) 
✔ 
✔ 
✔ 
✔ 
 
 
✔ 
 
 
Adverse events 
assessment 
 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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Mayo 
partial 
score 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
 
✔2 
Colonoscopy or 
sigmoidoscopy 
✔ 
 
 
✔ 
 
 
 
✔ 
✔2 
Endoscopic 
Mayo UC score 
✔ 
 
 
✔ 
 
 
 
 
✔2 
UCDAI 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
 
✔2 
CRP 
✔ 
✔ 
 
✔ 
 
 
✔ 
 
✔2 
C. diff / stool 
culture 
✔ 
 
 
 
 
 
 
 
 
Fecal 
calprotectin 
 
✔ 
 
✔ 
 
 
✔ 
 
✔2 
Comprehensive 
Metabolic panel 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔2 
Serum 
magnesium 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
 
Serum 
phosphorus 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
 
Tacrolimus level 
 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
 
Complete blood 
count 
✔ 
✔ 
 
✔ 
 
 
✔ 
 
✔2 
Development of 
Clostridium 
Difficile 
infection? 
 
 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔ 
Discontinuation 
of therapy? 
 
 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔ 
Assessment 
of 
Colectomy 
 
 
✔ 
✔ 
✔ 
 
✔ 
 
✔ 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: PRO00027931 
IRB Approval Period: 9/25/2018 – 2/26/2019 
 
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(1) “when needed” lab draws will be done to follow-up labs and adjust the drug if needed. 
They will be performed before the fourth or fifth dose after a change of tacrolimus 
dose.  Therapeutic drug monitoring: patients will be tested for tacrolimus and serum 
electrolytes (Na, K, Cl, phosphorus, creatinine, blood urea, magnesium) 
(2) Only if performed as a standard of care.  
 
 

Prot_SAP_002.pdf: 
 
 
 
 
 
 
 
 
 
 
Official Title: Induction Of Response And Remission Of Vedolizumab Monotherapy Vs. Combination 
Therapy With Tacrolimus In Patients With Moderately To Severely Active Ulcerative Colitis 
 
NCT02954159 
 
September 14, 2018 
 


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INDUCTION OF RESPONSE AND REMISSION OF VEDOLIZUMAB MONOTHERAPY 
VS. COMBINATION THERAPY WITH TACROLIMUS IN PATIENTS WITH 
MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS 
 
I) Research question: 
Does combination therapy of vedolizumab and tacrolimus increase the rate of clinical 
response and remission in patients with ulcerative colitis (UC) when compared to 
vedolizumab as monotherapy? 
 
II) Background: 
Anti-tumor necrosis factor (anti-TNF) agents have been approved by the FDA and 
proven to be efficacious in the induction and maintenance of both Crohn’s disease 
(CD) and ulcerative colitis (UC). They have also significantly changed the prognosis 
and natural history of the disease1. Unfortunately, a significant number experience 
primary or secondary failure of therapy.  
Natalizumab (NTZ), an alternative therapy for CD is a humanized monoclonal 
antibody against α4-β1 and α4-β7 integrin, which prevents migration of leukocytes 
into tissue. NTZ was shown to be more efficacious than placebo in inducing clinical 
response and remission in patients with CD2. Unfortunately, NTZ has been associated 
with an increased risk of developing progressive multifocal leukoencephalopathy 
(PML), limiting its use to patients with refractory disease.  
More recently, a new drug with a mechanism similar to NTZ has been studied and 
approved for the treatment of patients with CD and UC. Vedolizumab is a humanized 
monoclonal antibody to α4-β7 integrin that modulates intestinal (but not brain) 
lymphocyte trafficking. 
Phase III studies have shown that patients with UC who received vedolizumab had a 
higher rate of clinical response, clinical remission and mucosal healing when 
compared to placebo3. Nevertheless, while clinical response rate was almost 50%, the 
rate of clinical remission at 6 weeks was only 16.9. In comparison, in the ACT trials 
almost 40% of patients achieved remission at week 84. The delayed onset of action of 
vedolizumab monotherapy in patients with UC may lead to a higher colectomy rate 
and limit the use of vedolizumab in patients with active disease who require rapid 
induction of remission. Corticosteroids are used as a bridging agent to rapidly induce 
remission. However, we commonly see steroid refractory or dependent disease and 
steroid intolerance. Furthermore, steroids have devastating side effects. 
Tacrolimus inhibits the complexion of calcineurin with its respective cytoplasmic 
receptors cyclophilin and FK-binding protein 12 (FKBP-12), both of which regulate a 
calmodulin dependent-phosphatase. Tacrolimus has been found to be efficacious in 


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the treatment of patients with moderate to severe UC5. Unfortunately, because of the 
safety profile with long term use, the drug is mostly used as an induction agent.  
While switching to vedolizumab from another drug that has not been efficacious or 
has lost effectiveness (or starting vedolizumab as a first agent) can be beneficious in 
the long term, patients need an induction agent in order to achieve remission in a 
short period of time.  Tacrolimus is a widely used drug to prevent implant rejection 
after a transplant. Randomized controlled trials have shown that is highly effective 
with good response rates even after 2 weeks of therapy5. In order to avoid side effects, 
tacrolimus is usually used for a limited amount of time (12-14 weeks), which is 
sufficient time to induce remission of disease. Unfortunately, as other inflammatory 
bowel diseases, UC recurs and patients also require a maintenance therapy. While 
tacrolimus has been used with good results as a long term agent, the ideal scenario is 
to avoid its long term use as there is still a potential for side effects and a need for a 
very strict close monitoring 6. This is why a long term maintenance agent is needed to 
keep the patient in remission. Until recently, no ideal agent was available for this 
purpose as while anti-tumor necrosis factor agents (infliximab and adalimumab) 
have been approved for ulcerative colitis, its combination with another agent that 
induces systemic immunosuppression (in this case, tacrolimus) could potentially 
increase the risk of infections and/or malignancies.   Because vedolizumab is gut 
selective, does not affect the entire immune system and post-marketing studies have 
confirmed its safety profile7. This makes it a perfect combination agent to tacrolimus, 
theoretically decreasing the potential side effect while increasing its efficacy.  
 
Our hypothesis is that the addition of tacrolimus as an induction agent to a standard 
regimen of vedolizumab increases the efficacy of the drug, decreasing the rate of need 
for colectomy and other complications while quickly improving the patients’ quality 
of life without significantly increasing the risk of adverse events.  
 
III) Study Objectives 
The aim of this study is to assess if a combination therapy of tacrolimus and 
vedolizumab is superior to vedolizumab monotherapy for induction of remission in 
moderate to severe UC, and its effect on long and short-term outcomes including 
colectomy rate. Secondary aim of this study is to assess the safety of tacrolimus as an 
induction agent in patients with UC.  
 
IV) Relevance of the study 
Investigating concomitant agents to be used for a limited amount of time to rapidly 
induce remission may improve short and long-term outcomes, changing how we 
position vedolizumab in the treatment of UC and having it available as an equivalent 
(or potentially better) alternative to anti-TNFs. The use of an anti-TNF in combination 
with a calcineurin inhibitor is not feasible due to safety concerns. The exceptional 


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safety profile of vedolizumab and its gut selectivity makes it an ideal combination 
agent with tacrolimus. The proposed regimen combines the benefit of the rapid 
induction of remission effect that a limited course of tacrolimus has with the long 
term safety of vedolizumab, offering a considerable benefit over an anti-TNF.   
V) Study Population 
Inclusion criteria UC 
1. Patients aged 18 to 65 years with a confirmed diagnosis of UC.  
2. Patients with UC disease extent beyond 15 cm will be enrolled (must involve at 
least the sigmoid colon). 
3. Diagnosis of UC established at least 6 months before enrollment or evidence of 
chronicity in colonic biopsies. 
4. In female patients: 
o Post-menopausal for ≥1 year before screening, or 
o Surgically sterile, or 
o Agree to be on two contraceptive methods from the baseline visit 
through 4 weeks after discontinuing tacrolimus (or placebo), or 
o Completely abstain from heterosexual intercourse. 
5. In male patients:  
o Agreement not to father a child through 4 weeks after discontinuing 
tacrolimus (through contraception or abstinence). 
o If contraception is used by the patient, he will need to agree to be on 
two contraceptive methods from the baseline visit through 4 weeks 
after discontinuing tacrolimus (or placebo). 
6. Moderate to severe UC 
o Screening sigmoidoscopy with a Mayo endoscopic sub-score of 2 or 3, 
disease that extends beyond 15 cm from the anal verge; and one of the 
following: 
- 
Mayo Clinic partial UC score of 6 to 12 (Appendix 1).  
- 
Steroid dependent patients (Appendix 2). 
- 
Steroid intolerant (Appendix 2).  
7. Patients are planned to start vedolizumab as part of their clinical care.  
8. 5-aminosalicilates (oral or topical) are permitted as long as the dose is stable 
for at least 2 weeks before baseline 
9. Patients with or without previous exposure to anti-TNF agents can be included. 
Patients with previous exposure to anti-TNF must be off infliximab for 8 weeks 
and off adalimumab for 4 weeks or have an undetectable infliximab or 
adalimumab serum drug level with or without anti-drug antibody.   
10. Anti-diarrheals (eg, loperamide, diphenoxylate with atropine) for control of 
chronic diarrhea are not permitted in order to avoid confounding the 
evaluation of the patient. The patient must be off anti-diarrheal at the time of 
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11. The patient must have been off immunosuppressants (thiopurines or 
methotrexate) four weeks prior to baseline.   
12. Patients with previous Clostridium Difficile infection can be included as long as 
they received a full course of therapy and have a negative Clostridium Difficile 
PCR test and are infection free for 60 days prior to screening. 
Exclusion criteria UC 
1. Positive stool test for parasites or stool culture for pathologic bacteria within 
30 days prior to enrollment. 
2. Evidence or history of Clostridium Difficile infection within 60 days prior to 
enrollment. 
3. Active Cytomegalovirus (CMV) infection evidenced by a positive CMV PCR in 
serum and/or positive immunohistochemistry stain in colonic tissue. 
4. Uncontrolled hypertension. 
5. Chronic kidney disease (defined as a glomerular filtration rate < 60 mL/min, 
calculated using the Modification of Diet in Renal Disease (MDRD) formula) 
6. Chronic liver disease. 
7. A refractory electrolyte disorder (e.g. hypomagnesemia). 
8. Persistent hypomagnesemia that does not respond to oral magnesium 
supplementation defined as a value <1.3 mEq/L in two separate readings, 
despite the administration of oral magnesium [10 meq of slow-release 
magnesium chloride three times per day for 48 hours] within a week of 
baseline. 
9. Persistent hypophosphatemia defined as levels <2.2 mg/dL in two separate 
readings, 48 hours apart despite phosphate supplementation (sodium 
phosphate/potassium phosphate 500 mg up to three times daily for 48 hours) 
within a week of baseline. 
10.  Creatinine values of 1.5 mg/dL in 2 separate readings within a week of 
baseline. 
11. Established diagnosis of diabetes mellitus.  
12. Clinical or radiological evidence of megacolon.  
13. Intestinal perforation, or abdominal abscess within 3 months prior to baseline. 
14. Active clinically significant bacterial infection within 30 days of baseline. 
15. Personal history of total or sub-total colectomy. 
16. Current pregnancy or lactation. 
17. Unstable or uncontrolled medical disorder. 
18. Personal history of malignant neoplasm. 
19. Inability to give informed consent. 
20. History of alcohol or illicit drug abuse within 6 months of baseline visit.  
21. Patient that have received any experimental drug within 6 months of baseline 
visit.  
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23. Personal history of congenital or acquired immunodeficiency (eg, common 
variable immunodeficiency, human immunodeficiency virus [HIV] infection, 
organ transplantation) excluding pharmacologic immunosuppressant.  
24. Any of the following laboratory abnormalities during the screening period: 
a. Hemoglobin level <9 g/dL 
b. WBC count <3 × 109/L 
c. Lymphocyte count <0.5 × 109/L 
d. Platelet count <100 × 109/L or >1200 × 109/L 
e. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>2 × the upper limit of normal (ULN) 
25. To avoid interactions, patients on medications that induce or inhibit the 
Cytochrome p450 family 3, subfamily A (CYP3A) will be excluded. CYP3A 
inducers and inhibitors are shown in Appendix 3. 
 


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VI) Study Setting and Procedures 
Study setting 
Medical College of Wisconsin (WI, USA). This center sees a large volume of patients 
with IBD, including UC, and has an excellent structure to perform clinical research in 
IBD patients. This institution actively participates in several clinical trials, including 
multi-site studies.  
 
Study Procedures 
Pre-enrollment assessment / Screening (standard of care and within 2 weeks 
of enrollment) 
 
o The primary investigator will review the clinical, laboratory and endoscopic data 
for each candidate before enrollment. 
o The patient will be consented for the study 
o Urine Pregnancy test (women) 
o Sigmoidoscopy will be done within 2 weeks of starting vedolizumab. Biopsies will 
be obtained for immunohistochemistry for staining for CMV.  
o Extent of the disease should be documented, based on a full colonoscopy 
performed within the last 18 months.  
o In patients who are not on a stable dose of corticosteroids or who recently 
initiated corticosteroids (changes in dose or started steroids less than two weeks 
of screening), the sigmoidoscopy should be done 2-3 days prior to starting the 
investigational drugs to provide a more accurate assessment of disease severity 
at baseline entry into the trial. Both males and females will need to use two 
effective methods of contraception. 
o Demographics:  
o Age  
o Gender  
o Race  
o Ethnicity  
o Body Mass index recorded at admission. 
o 
Comorbidities 
o Prior exposure to medications 
- 
Prednisone 
- 
5-Aminosalicylates 
- 
Use of Azathioprine /6MP (and phenotype). 
- 
Use of Methotrexate 
- 
Use of anti-tumor necrosis factor agents 
o Exposures 
- 
Smoking status, classified as follow: 
o Current (at the time of screening) 


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o Remote 
o Never 
o Partial UC Mayo score (Appendix 3) 
o Blood tests including biochemical and serum inflammatory markers (all studies 
are standard of care. They are routine labs ordered in the clinic): 
- 
Complete blood count 
- 
Electrolytes 
o Sodium 
o Potassium 
o Magnesium 
o Chloride 
o Phosphorus 
- 
Total protein and albumin 
- 
Liver enzymes 
o Aspartate transaminase (AST) 
o Alanine transaminase (ALT) 
o Alkaline phosphatase (ALP) 
o Total bilirubin 
- 
Kidney function tests 
o Creatinine 
o Blood urea nitrogen (BUN) 
- 
C-Reactive protein (CRP) 
- 
Infliximab levels and antibodies when available 
- 
Adalimumab levels and antibodies when available.  
o Stool studies 
- 
Stool culture and ova and parasite  
- 
Clostridium Difficile PCR 
 
Baseline assessment (Week 0) (all studies are standard of care. They are routine 
labs ordered in the clinic): 
o Vital signs 
o Medications 
o CBC 
o Comprehensive Metabolic Panel (liver enzymes, kidney function tests and 
electrolytes) 
o Phosphorus 
o Magnesium 
o Total Cholesterol 
o Urine Pregnancy test (women) 
o Stool sample for fecal calprotectin  
o C-reactive protein (CRP) 


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o Partial and total UC Mayo score (Appendix 3) (endoscopic score calculated from 
screening sigmoidoscopy) 
o Ulcerative Colitis Disease Activity Index (UCDAI) (Appendix 4) 
o Begin vedolizumab (standard of care) 
o Begin study drug 
Week 2:  
o Vital signs 
o Urine Pregnancy test (women)  
o Medications 
o Comprehensive Metabolic Panel 
o Magnesium 
o Phosphorus 
o Tacrolimus levels 
o UC partial Mayo score 
o UCDAI 
o Adverse events 
o Study drug adjustment; maintenance phase starts upon site receipt of levels from 
this visit 
Week 6: (week 6 is a standard of care visit and CBC, CMP, and CRP at those visits are 
standard of care) 
o Sigmoidoscopy 
o UC endoscopic Mayo score (if applicable) 
o Vital signs 
o Medications 
o Urine Pregnancy test (women)  
o Fecal calprotectin 
o CBC  
o CRP 
o Comprehensive Metabolic Panel 
o Magnesium 
o Phosphorus 
o Tacrolimus levels 
o UC partial Mayo score 
o UCDAI 
o Adverse events 
 
Week 8: 
o Vital signs 
o Medications 
o Comprehensive Metabolic Panel 
o Magnesium 


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o Phosphorus 
o Tacrolimus levels 
o UC partial Mayo score 
o UCDAI 
o Adverse events 
 
Week 12 (phone call): 
o Stop study medication 
o Adverse events 
 
Week 14: (week 14 is a standard of care visit and CBC, CMP, and CRP at those visits 
are standard of care)  
o Vital signs 
o Medications 
o Urine Pregnancy test (women)  
o Fecal calprotectin 
o CBC  
o CRP 
o Comprehensive Metabolic Panel 
o Magnesium 
o Phosphorus 
o Tacrolimus levels 
o UC partial Mayo score 
o UCDAI 
o Adverse events 
 
Week 30 (phone call): 
o Adverse events (including colectomy and c diff status) 
o Concomitant medications 
 
When needed: 
Laboratories, tacrolimus levels, vital signs and other variables will be monitored in 
between the study visits as needed. For example, always after a change in tacrolimus 
dose, a tacrolimus level, magnesium, phosphorus and comprehensive metabolic panel 
will be performed.   
 
 
 


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Weekly phone call will be made to patients in order to assess for any new symptoms, 
including but not limited to: 
- 
Nausea/dizziness 
- 
Headaches 
- 
Seizures 
- 
Tremors  
- 
Hearing loss 
- 
Skin rash and/or pruritus 
- 
Respiratory symptoms including cough, shortness of breath and wheezing 
- 
Chest pain 
- 
Urinary symptoms  
- 
Decrease in urinary output 
- 
Arthralgias and/or myalgias 
- 
Jaundice 
 
Of note, the investigator performing dose adjustments for tacrolimus will not only 
receive laboratory values, but also a report of side effects. If he/she deems necessary, 
the patient will be called for a hospital visit to further assess symptoms independently 
of the decision made by the primary investigator. 
During the weekly call, the patient will also be asked regarding the start of any new 
drug and over the counter medication including herbs.  
 
 
 


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Study arms 
o Patients who meet inclusion criteria will be randomized 1:1 to receive: 
I) 
Treatment arm: vedolizumab at standard regimen with concomitant 
induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily).  
II) 
Placebo arm: vedolizumab at standard regimen with placebo. 
 
o Randomization will be concealed. When a patient is enrolled, the pharmacy at 
each clinical center will be contacted and randomization will be done in blocks of 
4. The patient, treating physician and investigator adjusting the dose of tacrolimus 
will be blinded to the therapy assignment. 
   
o The study will be blinded and neither the physician nor the patient will know to 
which arm the patients were randomly assigned. 
 
o All patients will receive intravenous vedolizumab 300 mg, at week 0 (baseline), 2 
and 6 followed by the same dose every 8 weeks. The drug will be given as per 
standard of care.  
 
o Tacrolimus (or placebo) will be started the day of the first vedolizumab infusion 
(+/- 24 hours).  
 
o Tacrolimus and placebo will be provided free of charge for the patient. Patients 
requiring magnesium and or phosphorus supplementation will also receive oral 
supplement free of charge. 
 
o 1 mg tacrolimus tabs will be provided to patients and adjustments will be 
performed over the phone. The target tacrolimus trough levels will be 10 to 15 
ng/ml in the first two weeks but can be reduced to 5-10 if the patient has side 
effect including tremors, low magnesium, headaches or abnormal kidney tests. 
After 14 days, the goal will be 5-10 ng/ml until the patient completes 12 weeks of 
tacrolimus (or placebo).  
 
o Both trial arms will come for lab work. The laboratory will communicate the 
results of tacrolimus levels, phosphorus, and magnesium kidney, liver tests, and 
electrolyte levels (comprehensive metabolic panel,), fecal calprotectin and CRP 
when applicable, to the study coordinator. The labs reported will depend on the 
visit. Because of the time some laboratories need to be processed, a 24 hour 
window will be permitted for reporting. 
 
o Tacrolimus levels will be tested 2 days (+/- 24 hours) after starting the drug and 
then 2 days (+/- 24 hours) after every dose adjustment, or as per discretion of the 
investigator performing dose adjustment. Then, patients will be tested once a 


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week  (+/- 24 hours) unless a change is made in dose, where a 2-day test will be 
performed.   
 
o Both study arms will have blood drawn for tacrolimus serum trough level. The un-
blinded research coordinator will submit the blood samples of the treatment 
group and control group for determination of tacrolimus level determined at the 
local lab. The research coordinator will then determine a hypothetical tacrolimus 
trough level for patients in the control group, using a tacrolimus dosing model, 
based on a steady-state infusion model, using clinical factors (age, ethnicity 
[African American or non-African-American), use of calcium channel blockers)8. 
The model will be programed in an Excel sheet and run by the coordinator.   
 
o The research coordinator will provide the investigator adjusting the tacrolimus 
level with the lab work results and relevant clinical information including blood 
pressure readings and a complete report of side effects (infection, hypertension, 
headaches, 
tremor, 
paresthesia, 
insomnia, 
diarrhea, 
nausea, 
vomiting, 
hyperkalemia, and hyperglycemia). The investigator will adjust the dose of 
tacrolimus based on these parameters. The investigator performing the 
adjustments is also responsible for determining the need for supplementation of 
magnesium or phosphorus.  
  
o The study site will have one investigator with experience in the management of 
tacrolimus and not involved in the care of these patients adjusting the tacrolimus 
dose based on the information above, which will be supplied by the local research 
coordinator. A backup investigator for dose adjustments will also be made 
available.  
 
o Because of the studies have shown that higher levels are associated with a much 
higher rate of response, the target tacrolimus level in the first 14 days (10–15 
ng/mL) then switch to maintain a level of 5–10 ng/mL for the rest of the 12 
weeks. 
 
o As a general rule, tacrolimus dose will be adjusted as follows in the first 14 days: 
- 
Tacrolimus whole blood concentration <5 ng/mL, 35% dose increase; 
- 
Tacrolimus whole blood concentration 5–9 ng/mL, 20% dose increase 
- 
Tacrolimus whole blood concentration 10–15 ng/mL, no change 
- 
Tacrolimus whole blood concentration 16–20 ng/mL, 40% dose decrease 
- 
Tacrolimus whole blood concentration 21–30 ng/ mL, hold the next dose 
of tacrolimus and then continue with a 60% dose decrease; 
- 
Tacrolimus whole blood concentration >30 ng/mL, hold tacrolimus until 
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- 
If serum creatinine values increase by 30% of the baseline, dose will be 
decreased by 35%. 
 
 
o In the maintenance phase, levels will can be maintained between 5 and 10 ng/ml 
if there are any side effects while on higher serum concentrations using the 
following strategy: 
- 
Tacrolimus whole blood concentration <5 ng/mL, 25% dose increase; 
- 
Tacrolimus whole blood concentration 5–10 ng/mL, no change 
- 
Tacrolimus whole blood concentration 11–15 ng/mL, 25% dose decrease 
- 
Tacrolimus whole blood concentration 16–20 ng/mL, hold the next dose of 
tacrolimus and then continue with a 60% dose decrease; 
- 
Tacrolimus whole blood concentration >20, hold tacrolimus until the next 
measurement (48 hrs.) 
- 
If serum creatinine values increase by 30% of the baseline, dose will be 
decreased by 35%.  
 
 
o Tacrolimus will be discontinued at week 12 (levels will still be measured up to 
week 14). 
 
Concomitant Medications 
o Steroids will be tapered immediately upon starting vedolizumab and tacrolimus. 
From 40 mg to 30 mg at week 1, then to 20 mg at week 2, to 15 mg at week 3, to 
10 mg at week 4 and 5 mg at week 5. Patients should be off steroids by week 6. 
This does not apply to patients not receiving steroids at the time of enrollment.  
o CYP3A inducers and inhibitors should not be taken. (Appendix 3) 
o The investigator performing study drug adjustments is also responsible for 
determining the need for supplementation. Complete stopping criteria are found 
in section IX, guidelines as follows  
- 
Persistent hypophosphatemia defined as levels <2.2 mg/dL in two 
separate readings, 48 hours apart despite phosphate supplementation 
(sodium phosphate/potassium phosphate 500 mg up to three times daily).  
- 
Persistent hypomagnesemia that does not respond to oral magnesium 
supplementation defined as a value <1.3 mEq/L in 2 separate readings in 
two separate readings, 48 hours apart and while on oral magnesium 
supplementation [10 meq of slow-release magnesium chloride three times 
per day]. 
Vaccination considerations 
Non-live vaccines including parenteral influenza vaccine, hepatitis A and B and 
pneumonia vaccines can be received. The use of live vaccines should be avoided 
during treatment with tacrolimus; examples include (not limited to) the following: 


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intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, 
and TY21a typhoid vaccines. 
 
Duration of the study 
o The patient will be considered to complete the study at week 14 during the visit. 
No intervention will be made after week 14 except for monitoring. Nevertheless, 
will continue to be monitored as per standard of care and at week 30 assessment 
will also be performed including clinical disease activity, need for colectomy, UC 
medications.  
 
VII) Statistical analysis 
Sample size 
This study will include 10  patients per arm (for a total of 20 patients). This is a pilot 
study to assess different response rates. Sample size was calculated assuming that 
80% of patients will achieve the primary outcome at week 6 in the tacrolimus and 
vedolizumab group and 20% will achieve the outcome in placebo and vedolizumab 
group.  
Analyses 
Descriptive statistics (mean or median ± standard deviation for continuous variables 
and count/percentages for categorical variables) will summarize baseline 
characteristics (demographic and clinical) in aggregate as well as across arms. 
Primary outcome analyses will employ an independent two-sample test for binomial 
proportions to compare (a) the rate(s) of remission at week 6 and the secondary 
outcomes.  Each of these outcomes will be analyzed separately and we will not adjust 
for multiple tests as each outcome carries equal weight.   Analyses will use the intent-
to-treat dataset, but sensitivity analyses will be performed on the per protocol 
dataset.  Additional analyses will employ a log-rank test to compare time-to-
remission across arms.  Analyses will explore relationship between baseline 
characteristics (age, gender, CRP, smoking history, etc.) and outcome(s) in order to 
evaluate potential confounding or interaction effects via a series of logistic regression 
models.   
Secondary outcome analyses will further utilize the independent two-sample test for 
binomial proportions for categorical variables, and the independent two-sample t-
test for continuous variables (CRP, UC Mayo score, IBDQ, etc.) across arms at relevant 
study time points. Nonparametric methods and/or transformation of variables may 
be used as appropriate (i.e., when statistical assumptions of parametric tests on 
untransformed variables are not met or questionable).   
 


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VIII) Risks 
Safety 
Safety assessments included vital signs, physical examinations and laboratory 
analysis during each visit. Patients who discontinue the treatment will continue to be 
followed as per protocol. Follow-up will be discontinued in patients who withdraw 
informed consent or are lost for follow-up.  
- 
For adverse reactions: the following items will be analyzed: 
o The incidence and type of any clinical adverse reaction.   
o The incidence and type of known clinical adverse reactions    
o The incidence and type of any non-clinical adverse reaction 
o The incidence and type of known non- clinical adverse reactions. 
Both vedolizumab and tacrolimus have warnings in the label for the risk of 
progressive multifocal leukoencephalopathy (PML). There have been some potential 
reports of PML associated with immunosuppressant drugs including tacrolimus. 
There is also a potential risk with vedolizumab, even though to the date this protocol 
was written, no cases have been reported. Patients will be monitored for any new 
onset, or worsening, of neurological signs and symptoms, including the typical signs 
and symptoms associated with PML that are diverse, progress over days to weeks, 
and include progressive weakness on one side of the body or clumsiness of limbs, 
disturbance of vision, and changes in thinking, memory, and orientation leading to 
confusion and personality changes.  Since the progression of deficits usually leads to 
death or severe disability over weeks or months, the study drug(s) will be stopped 
immediately if PML is suspected, and the patient will be referred to a 
neurologistPatient confidentiality:  
To protect patient confidentiality, databases with personal identifiers will be stored 
on secure servers with restricted and audited access.  
 
IX) Regulatory 
Institutional review board (IRB) approval will be acquired from the Medical College 
of Wisconsin(MCW) prior to commencement of study activities. Guidelines for Good 
Clinical Practice (GCP), as described in ICH Guideline E6, will be followed. The 
investigator will conduct this study in accordance with applicable national, state, and 
local laws of pertinent regulatory authorities, and FDA’s regulations 21 CFR 312, part 
50, 54, and 56.  
The Investigator will be responsible for regulatory compliance and ongoing timely 
reporting of annual reports, protocol deviations and serious adverse events to the 
respective IRB. The Principal Investigator at Medical College of Wisconsin will comply 
with any necessary reporting to the FDA and study sponsor within the timelines 
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This study has the benefit of testing a drug that has been approved by the federal drug 
agency (FDA) for the treatment of UC. Tacrolimus, while not FDA approved for the 
treatment of UC, was shown to be efficacious in prior clinical trials5.  
 
Quality Control and Data Management 
A data safety monitoring board will be assigned. The committee members will include 
participants who are not involved in the study and will overlook the safety of the 
study agent. For that purpose, un-blinded safety data will be available to the 
committee. 
The investigator is responsible for ongoing review of the data quality and compliance 
to protocol. The PI will conduct ongoing quality checks or assign study team members 
for ongoing reviews to ensure data integrity and accuracy. Any unexpected deviations 
will be corrected and reported in a timely manner per IRB requirements.  
 
X) Outcomes 
Primary Outcome 
o Steroid-free clinical response at week 6 after starting vedolizumab, defined as 
a reduction in the Mayo Clinic score of at least 3 points and a decrease of at 
least 30% from the baseline score with a decrease of at least 1 point on the 
rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1 while off 
steroids. Oral budesonide will be considered steroid use. If the patient is 
steroid-dependent by week 6 (Appendix 1), will be considered to have failed 
the primary outcome. 
 
Secondary Outcomes 
o Steroid-free clinical response at week 14 after starting vedolizumab. 
o Steroid-free Clinical remission at week 6 defined as either:   
o Mayo clinic score <3 with: 
 Stool Frequency sub-score <2 
 Rectal Bleeding sub-score <2 
 Endoscopy sub-score = 0 or 1 (on Mayo Score)  
o Steroid-free Clinical remission at week 14 defined as:   
o Mayo clinic score <3 with: 
 Stool Frequency sub-score <2 
 Rectal Bleeding sub-score <2 
o Change in CRP at week 6 and 14. 
o Change in fecal calprotectin at week 14. 
o Endoscopic remission evaluated between weeks 12 and 16 defined as an 
endoscopic Mayo score of 0 or 1.  


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o Colectomy-free survival at week 14 and 30. 
o Clostridium Difficile infection. 
o Any infection including bacterial, viral or fungal as per investigator. 
o Kidney injury defined as a 30% increase in creatinine.  
o Other side effects (tremor, headaches, etc.) 
Exploratory Outcomes 
o Starting another therapy for UC by week 30.  
o Durable clinical remission measured at week 30 and defined as: 
- 
Continuation of vedolizumab 
- 
Colectomy-free 
- 
Steroids-free 
- 
No need for salvage therapy with cyclosporine/tacrolimus 
 
 
o Durable endoscopic remission measured at week 30 and defined as: 
o Continuation of vedolizumab 
o Colectomy-free 
o Endoscopic remission (Mayo endoscopic score ≤1). 
o Steroids-free  
o No need for salvage therapy with cyclosporine/tacrolimus 
 
Consideration about outcomes  
- 
Recurrence of symptoms with a negative C. Diff PCR stool test while off 
steroids will be considered as a failure of therapy. 
- 
The need for a course of steroids, inability to taper off steroids due to 
symptoms or a colectomy due to active disease will also be considered a 
treatment failure. The decision to change this management will be perform 
per standard of care by the patient’s primary gastroenterologist (who will 
be blinded to the drug/placebo assignment).  
 
Follow-up and assessment of outcomes (Appendix 5) 
o Patients will be evaluated at baseline, and then at week 0, 2, 6, 8 and 14.  
o A long term follow-up (week 30) will also be done. 
o Visits at week 6 and 14 will be done as part of the standard of care. The 
research coordinator will extract laboratory and clinical information from 
that visit to populate the database and communicate it to the external 
investigator adjusting doses.  
o Additional laboratory visits may be needed. An average of 32 total lab 
assessment are estimated per patient. 
 
 


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XI) Safety and Data Monitoring  
The Investigator will monitor the conduct of protocol on a continuous basis for 
expected and unexpected patient’s safety related issues. The PI will appoint a Data 
Safety Monitoring Board. Members of this board will be independent of study team 
and will overlook the safety of the study agent.  For that purpose, un-blinded safety 
data will be available to the committee.  
Annual reports will be submitted to the IRB. Severe or unanticipated adverse events 
will be reported immediately to the IRB, DSMB and FDA within timelines suggested 
by each of these regulatory bodies. 
Risks of the Study Medication: 
Tacrolimus (formerly known as FK506) was described in the treatment of various 
immune-mediated diseases including Crohn’s disease, rheumatoid arthritis, uveitis, 
nephrotic syndrome, psoriasis, and lupus membranous nephritis, among others. It is 
also widely used to prevent post-transplant allograft rejection. While the drug is 
associated with several side effects, these are usually seen in transplant patients. 
Previously described potential side effects by system: 
- 
Nephrotoxicity: patients may develop a raise in serum creatinine, which is 
usually reversible when decreasing or discontinuing the drug. Chronic 
renal damage is almost never seen in patients on short courses of therapy. 
In a study done in patients with UC for 29 weeks, none developed elevation 
of the creatinine. In a randomized controlled trial looking at the efficacy of 
tacrolimus in UC, the authors reported that 4-5% of patients receiving the 
drug developed an elevation of creatinine >30% of the baseline. No one 
developed severe kidney injury. In our study, renal function will be 
monitored carefully, and doses will be decreased if there is an increase of 
30% or more of the baseline creatinine or discontinued if the creatinine 
reaches 1.5 mg/dL.   
- 
Hypertension: tacrolimus may raise the blood pressure. Patients with a 
known diagnosis of hypertension at baseline, will not be included. Blood 
pressure will be monitored throughout the study and on every visit. If 
blood pressure reaches 140/90 mmHg (sustained, appropriately 
measured during 2 consecutive visits), the drug will be adjusted. If the 
blood pressure at any time is higher than >160/100 mmHg, the drug will 
be decreased without waiting for a second reading. If despite the dose 
reduction, blood pressure continues to be >160/100 and there is no 
alternative plausible etiology, the drug will be discontinued due to side 
effects. A reading of >160/100 was set as a limit as it is considered 
“moderate hypertension”9.  
- 
Neurological side effects. Tremors are a common side effects of tacrolimus, 
and are usually transient, even without dose adjustment. Rarely, patients 
may develop headaches. If patients in our study develop headaches or 
tremors, the severity of the symptoms will be assessed with an appropriate 


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dose reduction. Studies have shown mild tremors in up to 20% of patients 
and headaches in about 5%5. Seizures were previously reported, but they 
are usually seen with IV administration of the drug and patients with 
previous history of seizures will be excluded from the study.  
- 
Metabolic abnormalities. Tacrolimus may cause hyperglycemia. Patients 
with diabetes mellitus will be excluded from our study, and glucose levels 
will be measured every follow-up. No severe cases of hyperglycemia have 
been reported.  
- 
Rare side effects: anorexia, nausea, vomiting, diarrhea, and abdominal 
discomfort. Increased liver enzymes are reversible with dose reduction or 
drug discontinuation. Patients with elevation of AST, ALT or ALP more than 
two times the upper limit of normal will be excluded.  
- 
Infections: there is a theoretical risk of infections in patients on 
immunosuppressants. If the patient develops any infection that warrants 
admission, the drug will be discontinued until the infection is cleared.  
- 
Reproductive side effects: tacrolimus is a FDA category C drug and while it 
could be used in pregnant patients in some cases, for the purpose of this 
study, pregnant patients or those planning for pregnancy in 6 months 
following enrollment will be excluded.  
 
Any of the above mentioned side effect for event grade 3 or more per 
CTCAE guidelines must be reported to the Sponsor-Investigator within 24 
hours of learning of the event. Any serious adverse events (an adverse 
event that (1) results in death, (2) is life threatening, 
(3) requires inpatient hospitalization or prolongation of existing 
hospitalization, 
(4) 
results 
in 
persistent 
or 
significant 
disability/incapacity, (5) results in a congenital anomaly/birth defect, or 
(6) is an important medical event that jeopardizes the subject or requires 
medical intervention to prevent one of outcomes listed above) must be 
reported to the Sponsor-investigator within 24 hours of study staff 
learning the event. 
The Sponsor-investigator will further evaluate the event and its 
seriousness and suggest further course of actions. 
 
Reportable events must be submitted to regulatory agencies as mentioned in the 
Regulatory section below. 
 
Individual stopping criteria: 
- 
Development of a lymphoma or any malignancy, independently if it may 
any relation with the study drug.  
- 
Development of any infection that meets criteria for a Grade 3, Common 
Terminology Criteria for Adverse Events v4.0 (CTCAE). 


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- 
Persistent hyperkalemia defined as values ≥5.5 mEq/L in two separate 
readings, 48 hours apart. 
- 
Persistent hypomagnesemia that does not respond to oral magnesium 
supplementation defined as a value <1.3 mEq/L in 2 separate readings in 
two separate readings, 48 hours apart and while on oral magnesium 
supplementation [10 meq of slow-release magnesium chloride three times 
per day]. 
- 
Persistent hypophosphatemia defined as levels <2.2 mg/dL in two 
separate readings, 48 hours apart despite phosphate supplementation 
(sodium phosphate/potassium phosphate 500 mg up to three times daily).  
- 
Creatinine values of 1.5 mg/dL in 2 separate readings.  
- 
Development of acute kidney injury defined as per Acute Kidney Injury 
Network (AKIN) diagnostic criteria within 48 hours of starting the drug:  
o Absolute increase in the serum creatinine concentration of ≥0.3 mg/dL 
from baseline 
o Percentage increase in the serum creatinine concentration of ≥50 
percent, or 
o Oliguria of < 0.5 mL/kg per hour for more than six hours. 
- 
Any hypersensitivity reaction attributed to the tacrolimus as per treating 
physician. 
- 
Blood pressure at any time >160/100 mmHg will trigger a tacrolimus dose 
reduction by 35%. If in a second reading, it persists >160/100 mmHg, 
tacrolimus will be discontinued.  
- 
Development of elevated liver enzymes (AST/ALT) 3 times higher than the 
upper limit of normal and/or the development of a bilirubin ≥1.9 mg/dL 
without any other potential explanation (starting another pharmacologic 
therapy, new-onset hepatitis infection or other causes including alcohol 
intake). If there is no evident etiology is found, the drug will be stopped 
and liver enzymes followed twice weekly until they normalize. 
- 
Development of a Grade 3 adverse event attributed to the use of tacrolimus 
defined as severe or medically significant but not immediately life-
threatening adverse event including hospitalization or prolongation of 
hospitalization; disabling; limiting self care activities of daily living. Based 
on known potential side effects of tacrolimus some of the events that can 
trigger discontinuation of the drug in the patient include: 
o Seizures 
o Severe infection requiring admission to a hospital 
o Hypersensitivity reaction 
o Any CTCAE grade 3 effect that has any potential association with the 
use of tacrolimus as described in the current FDA label.  
- 
Development of pure red cell aplasia: while is a potential complication, we 
also need to consider patients with moderate to severe ulcerative colitis 
present almost universally with anemia and present with loss of blood 
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(hemoglobin <7 gr/dL) that does not respond to iron supplementation and 
with no other potential cause will be considered pure red cell aplasia. 
- 
If the patient presents with classic symptoms of hyperglycemia (thirst, 
polyuria, weight loss, blurry vision) and has a random blood glucose value 
of 200 mg/dL and off steroids, the study drug will be discontinued.  
- 
If a random glucose measurement is ≥200 mg/dL, but the patient has no 
symptoms, he/she will be monitored with glucose levels weekly and the 
study drug will be discontinued if the level reaches ≥200 mg/dL in two 
more occasions, tacrolimus/placebo will be discontinued 
- 
In the event of starting any new therapy or required a colectomy for the 
ulcerative colitis, the patient should be discontinued from the study and 
will be considered to fail to achieve the study outcome. 
- 
Development of new or worsening neurological symptoms will prompt 
immediate evaluation. If there is even a minimal clinical suspicious for 
PML, both drugs (tacrolimus and vedolizumab) will be discontinued.  
- 
The patient will be able to withdraw at any time.  
 
Termination of the study 
 
- 
If two or more patients develop the same Grade 3 CTCAE v4.0 adverse 
event attributed to the use of tacrolimus defined as severe or medically 
significant but not immediately life-threatening adverse event including 
hospitalization or prolongation of hospitalization; disabling; limiting self-
care activities of daily living.  
- 
Any Grade 4 CTCAE v4.0 with potential relationship with the use of 
tacrolimus.  
 
Assessment and monitoring adverse events 
o As detailed in the “Study Procedures” section above, adverse events will be 
monitored with each visit and weekly trough a phone call to the patient.  
 
o Any side effect for event grade 3 or more per CTCAE guidelines will be reported 
to the Investigator within 24 hours of learning of the event. Any serious adverse 
events (an adverse event that (1) results in death, (2) is life threatening, (3) 
requires inpatient hospitalization or prolongation of existing hospitalization, (4) 
results in persistent or significant disability/incapacity, (5) results in a congenital 
anomaly/birth defect, or (6) is an important medical event that jeopardizes the 
subject or requires medical intervention to prevent one of outcomes listed above) 
will be reported to the investigator within 24 hours of study staff learning the 
event. The investigator will further evaluate the event and its seriousness and 
suggest further course of actions. Side effect will also be communicated to the 
sponsor. 


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o If the patient develops an infection (any but Clostridium Difficile) that meets a 
grade 3 or more per CTCAE, the drug will be discontinued. For infections that meet 
grade 1 or 2 criteria, tacrolimus/placebo will be held until a full course of 
antibiotics are given. Then, the drug/placebo will be resumed at the same dose 
the patient was receiving. If the same infection recurs, tacrolimus/placebo will be 
discontinued.  
 
o Because of how common Clostridium Difficile can develop in patients with UC and 
because is usually seen with active disease, if the patient develops worsening 
symptoms and tests positive, treatment will be started as per standard of care. If 
the 
infections 
warrants 
admission 
(as 
per 
the 
patient’s 
primary 
gastroenterologist), then tacrolimus/placebo will be held until two weeks of 
therapy are completed. 
 
o An assessment of attribution of adverse events will be performed and each 
classified as below based on several factors including known adverse event of the 
drug, temporal relationship to the initiation of the drug and serum drug level and 
clinical assessment.  
- 
Definite (clearly related to) 
- 
Probably (likely related to) 
- 
Possible (may be related to) 
- 
Unlikely (doubtfully related to) 
- 
Unrelated (clearly not related to) 
 
o All the adverse events noted during the study should be followed until resolution 
or return to baseline levels. 
 
 


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Appendix 1: Mayo UC Score 
 
Stool frequency 
0 = Normal number of stools for this patient  
1 = 1–2 stools more than normal 
2 = 3–4 stools more than normal 
3 = 5 or more stools more than normal 
 
Rectal bleeding 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time  
2 = Obvious blood with stool most of the time 
3 = Blood alone passed 
 
Mucosal appearance* 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern, mild friability) 
2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions)  
3 = Severe disease (spontaneous bleeding, ulceration) 
 
Physician’s global assessment 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
 
(*) Partial UC Mayo score excludes the “mucosal appearance item”. 
 
 


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Appendix 2: Definition of steroid dependent or intolerance 
 
- 
One or more failed attempt(s) to taper corticosteroids to/below a dose equivalent 
to prednisone 10 mg daily orally on 2 separate occasions. 
 
- 
History of intolerance of corticosteroids (including, but not limited to Cushing’s 
syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection). 
 
 
 


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Appendix 3: CYP3A inducers and inhibitors 
CYP3A inducers 
Bexarotene 
Bosentan 
Carbamazepine 
Dabrafenib 
Dexamethasone 
Efavirenz 
Enzalutamide 
Eslicarbazepine 
Etravirine 
Fosphenytoin 
Lumacaftor  
Mitotane 
Modafinil 
Nafcillin 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin (rifampicin) 
Rifapentine 
St. John’s wort 
 
CYP3A inhibitors 
Amiodarone 
Aprepitant 
Atazanavir 
Boceprevir 
Ceritinib 
Clarithromycin 


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Cobicistat and cobicistat containing coformulations 
Conivaptan 
Cyclosporine 
Darunavir 
Diltiazem 
Dronedarone 
Erythromycin 
Fluconazole 
Fosamprenavir 
Grapefruit juice (food) 
Idelalisib 
Imatiib 
Indinavir 
Isavuconazole 
Itraconazole 
Ketoconazole 
Lopinavir 
Mifepristone 
Nefazodone 
Nelfinavir 
Netupitant 
Nilotinib 
Ombitasvir-paritaprevir-ritonavir 
Ombitasvir-paritaprevir-ritonavir plus dasabuvir 
Posaconazole 
Ritonavir and ritonavir containing coformulations 
Saquinavir 
Schisandra 
Telaprevir 
Telithromycin 
Verapamil 


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Voriconazole


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Appendix 4: Ulcerative Colitis Disease Activity Index (UCDAI) 
 
Stool frequency 
0 = Normal number of stools for this patient  
1 = 1–2 stools/day > normal 
2 = 3–4 stools/day > normal 
3 = >5 stools/day > normal 
 
Rectal bleeding 
0 = No blood seen 
1 = Streaks of blood  
2 = Obvious blood  
3 = Mostly blood 
 
Mucosal appearance* 
0 = Normal or inactive disease 
1 = Mild friability 
2 = Moderate friability  
3 = Exudation, spontaneous bleeding 
 
Physician’s global assessment 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
 
Maximum Score= 12 
 
 


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Appendix 5: Schedule of Events 
 
Schedule of 
events 
Pre-
treatment 
 
 
Treatment 
Follow 
Up 
Screening 
Week 
0 
Week 
2 
Week 
6 
Week 
8 
 Week 
12 
Week 
14 
When 
needed
1 
Week 
30 
Informed 
Consent 
✔ 
 
 
 
 
 
 
 
 
Begin tacrolimus 
 
✔ 
 
 
 
 
 
 
 
Begin 
vedolizumab 
 
✔ 
 
 
 
 
 
 
 
Stop tacrolimus 
 
 
 
 
 
✔ 
 
 
 
Prior 
medications 
✔ 
 
 
 
 
 
 
 
 
Concomitant 
medications 
 
✔ 
 
 
✔ 
✔ 
✔ 
 
✔ 
 
✔ 
Demographics 
✔ 
 
 
 
 
 
 
 
 
Smoking status 
✔ 
 
 
 
 
 
✔ 
 
 
Medical/surgical 
history 
✔ 
 
 
 
 
 
 
 
 
Vitals signs  
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔2 
Body mass (Kgs) 
✔ 
✔ 
 
 
 
 
 
 
 
Urine pregnancy 
test (women) 
✔ 
✔ 
✔ 
✔ 
 
 
✔ 
 
 
Adverse 
events 
assessment 
 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 


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Mayo 
partial 
score 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
 
✔2 
Colonoscopy or 
sigmoidoscopy 
✔ 
 
 
✔ 
 
 
 
✔ 
✔2 
Endoscopic 
Mayo UC score 
✔ 
 
 
✔ 
 
 
 
 
✔2 
UCDAI 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
 
✔2 
CRP 
✔ 
✔ 
 
✔ 
 
 
✔ 
 
✔2 
C. diff / stool 
culture 
✔ 
 
 
 
 
 
 
 
 
Fecal 
calprotectin 
 
✔ 
 
✔ 
 
 
✔ 
 
✔2 
Comprehensive 
Metabolic panel 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔2 
Serum 
magnesium 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
 
Serum 
phosphorus 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
 
Tacrolimus level 
 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
 
Complete blood 
count 
✔ 
✔ 
 
✔ 
 
 
✔ 
 
✔2 
Development of 
Clostridium 
Difficile 
infection? 
 
 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔ 
Discontinuation 
of therapy? 
 
 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔ 
Assessment 
of 
Colectomy 
 
 
✔ 
✔ 
✔ 
 
✔ 
 
✔ 


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(1) “when needed” lab draws will be done to follow-up labs and adjust the drug if 
needed. They will be performed before the fourth or fifth dose after a change 
of tacrolimus dose.  Therapeutic drug monitoring: patients will be tested for 
tacrolimus and serum electrolytes (Na, K, Cl, phosphorus, creatinine, blood 
urea, magnesium) 
(2) Only if performed as a standard of care.  
 
 
 


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