A Randomized DoubleBlind Phase 4 Study to Evaluate the Safety and Proportion of Subjects With
Fistula Healing in 2 Dose Regimens of Entyvio (Vedolizumab IV) in the Treatment of Fistulizing
Crohn*s Disease (ENTERPRISE)

Crohn Disease (CD) is focal, may be transmural, and can involve any segment of
the gastrointestinal tract from mouth to anus. CD is neither medically or
surgically curable at the current time. Fistulizing disease complicates CD in
up to 40% of patients. Patients with fistulizing CD experience symptoms of anal
pain, purulent discharge, and incontinence, which result in high morbidity and
impaired quality of life.

Fistulae rarely heal spontaneously and usually require medical therapy or
surgery. Although a range of medical and surgical options is available for CD,
the management of perianal CD is challenging and often requires a comprehensive
approach including medical and surgical interventions. Well-designed
prospective clinical trials specific to the fistulizing CD patient population
are needed. The current study will generate meaningful data with vedolizumab IV
in the treatment of perianal fistula(e) and is expected to provide guidance on
an optimal dose regimen for this complex patient population.

Vedolizumab IV is approved for the treatment of adult patients with moderately
to severely active UC and CD in several regions, including the United States
and European Union.

Primary Objectives:
To evaluate the proportion of subjects with fistula healing at Week 30 with 2
different dose regimens of vedolizumab IV 300 mg in subjects with perianal
fistulizing CD.

Secondary Objective:
To evaluate fistula healing over a 30-week evaluation period.

This is a phase 4 randomized double-blind multicenter study to evaluate the
safety and the proportion of subjects with fistula healing in 2 dose regimens
of Entyvio (vedolizumab IV) over a 30-week treatment period (with the last dose
at Week 22). Approximately 100 subjects with moderately to severely active
Crohn*s disease (CD) with 1 to 3 draining perianal fistula(e) will be enrolled.
Subjects must have historically had an inadequate response with, lost response
to, or been intolerant to either conventional therapy or a tumor necrosis
factor-alpha (TNF-α) antagonist for their underlying CD to be eligible.
Subjects will be followed for a total of 48 weeks.

Group 1: Vedolizumab IV 300 mg dose at Weeks 0, 2, 6, 14 and 22, and a placebo
infusion at Week 10.
Group 2: Vedolizumab IV 300 mg dose at Weeks 0, 2, 6, 10, 14 and 22.

Participants will be required to take oral antibiotic medication from Day 1
till Week 6.

All drugs have the possibility of complications and undesirable side effects
that are unknown at this time and could possibly occur. There may be risks from
the study medication to an unborn child or breast-feeding infant that are not
currently known.

As of 19 november 2016 approximately 4200 subjects have received at least 1
dose of , vedolizumab in clinical trials and approximately 1832 subjects have
received 12 months of vedolizumab in clinical trials. In IV studies to date,
vedolizumab has been well tolerated.
The most common side effects from controlled clinical trials, reported in 10% -
20% of patients, include:

• worsening of Crohn*s disease in patients with Crohn*s disease.
• worsening of ulcerative colitis in patients with ulcerative colitis
• common cold
• headache
• joint pains

No side effects have been seen in more than 20% of subjects who received at
least 1 dose of vedolizumab.
Other side effects, reported in 2-9% of patients, include:

• nausea.
• fever.
• stomach pain.
• upper respiratory tract infection.
• tiredness.
• vomiting.
• low levels of red blood cells (anemia).
• cough.
• back pain.
• bronchitis
• flu.
• urinary tract infection.
• dizziness.
• diarrhea.
• sinus infection.
• flu-like illness.
• rash.
• sore throat.
• itching.
• swollen ankles.
• pains in arms or legs.
• stomach flu.
• an infected cavity filled with pus near the anus or rectum (anal abscess).
• small tunnel which connects an infected gland inside the anus to an opening
on the skin around the anus (anal fistula).


Since many of these symptoms are commonly reported in patients with UC or CD,
it is unclear which may be related to vedolizumab, which may be related to the
underlying illness, and which may have occurred by chance.
In addition to the risks listed above, vedolizumab and study procedures may
have unknown risks.
As with any drug, allergic reactions may occur. If you have a very bad allergic
reaction, you could die. Some things that happen during an allergic reaction
are:

• a rash (reddening or blistering of the skin).
• difficulty breathing.
• wheezing when you breathe.
• sudden drop in blood pressure.
• swelling around the mouth, throat, or eyes.
• fast pulse.
• sweating.

There is a possibility of a greater chance of getting an infection, difficulty
fighting off an infection, or reactivation of an old infection. Serious
infections have occurred. There is a possibility that treatment with
vedolizumab could cause reactivation of an old infection such as tuberculosis
(TB).

Patients with inflammatory bowel disease have an increased risk for colon
cancer, and some of the drugs that are currently being used for treating CD and
UC can increase the risk of certain cancers. Less than 1% of patients who
received vedolizumab as part of the UC and CD studies were diagnosed with
cancer, including colon cancer. It is also not known whether the events of
cancer happened by chance or whether vedolizumab was a contributing factor.

No cases of Progressive Multifocal Leukoencephalopathy (PML) , a serious and
sometimes fatal brain infection, have been reported in people receiving
vedolizumab. There is currently not enough information to know if vedolizumab
will increase the risk of PML and a risk of PML cannot be ruled out.

Deaths have occurred in patients participating in vedolizumab clinical trials.
The details of these cases were reviewed by an Independent Safety Monitoring
Board that oversaw the safety of these patient studies. No changes in
monitoring of the trials were recommended by the Board.


Risks associated with infusion site reactions (IV administration)
Symptoms associated with an infusion site reaction may include redness,
tenderness, warmth, itching, or discomfort. An additional risk could occur as a
result of the medication leaking out from the blood vessel where it was infused
which would cause pain, blistering, and severe skin damage.

Risks associated with Electrocardiograms (ECGs)
There is no pain or discomfort during an ECG; however the patches may cause a
skin reaction such as redness or itching. Taking the pads off may cause
localized irritation to the skin and/or hair loss, similar to having a bandage
taken off.

Risks associated with blood draws
Although rare, excess bleeding, clots and infections at the injection site may
occur. Lightheadedness and/or fainting may also occur during or shortly after
the blood is taken.

Risks associated with an MRI
The risks and discomforts associated with the MRI test are:
• Nausea, vomiting, bloating, or rectal irritation caused by the bowel cleanse
prep (common).
• Abdominal bloating (common) from drinking fluid prior to scan.
• Discomfort from lying on the scanner table or the noise during the scan.
• Feeling of being closed in while in the large tube of the scanner
(claustrophobic). If you feel too claustrophobic, the test can be stopped.
• Allergic reaction to medication used to slow bowel motion (rare).
• Potential side effects of injected MRI contrast agent.
• Irritation, bruising or infection (rare) at the injection site for the bowel
medication or MRI contrast.

Risks associated with a brain MRI
• Discomfort from lying on the scanner table or the noise during the scan.
• Feeling of being closed in while in the large tube of the scanner
(claustrophobic). If you feel too claustrophobic, the test can be stopped.
• Potential side effects of injected MRI contrast agent.
• Irritation, bruising or infection (rare) at the injection site for the MRI
contrast.


Risks associated with spinal tap
• Bleeding into the spinal canal.
• Discomfort during the test.
• Headache after the test.
• Hypersensitivity to the anesthetic.
• Infection introduced by the needle.
• Increased risk of bleeding for people that take blood thinners.
• Nerve damage

Pregnancy, contraception and breastfeeding
There may be risks from the study medication to an unborn child or
breast-feeding infant that are not currently known. Rarely, there have been
reports of birth defects in children born to women who were exposed to
vedolizumab. We do not know whether the birth defects are related to the use of
vedolizumab. Due to unknown risks and potential harm to the unborn child/
infant, patients should not become pregnant, nurse a baby, or father a child
while participating in this study and for 18 weeks after their last dose.