A Phase 2b, Extension Study to Determine the Long-term Safety of Vedolizumab IV in Pediatric Subjects With Ulcerative Colitis or Crohn*s Disease.;(Long-term Safety With Vedolizumab IV in Pediatric Subjects With Ulcerative Colitis or
Crohn*s Disease)

Takeda Development Centre Europe Ltd., the study Sponsor, is paying the study
hospital and the study doctor to carry out this research study. Approximately
80 children from 2-17 years old from about 72 study centers from around the
world will take part in the research study. Approximately half will have CD and
the other half will have UC.

Vedolizumab, the study drug, has been approved in several regions, including
the United States (US) and European Union (EU) for the treatment of adult
patients with moderately to severely active CD or UC who have had an inadequate
response to, loss of response to, or intolerance to conventional treatments.

The use of vedolizumab in children has not been approved by regulatory agencies
and therefore when used during research it is considered an investigational
drug. Vedolizumab has not yet been tested in children in a research study.
Vedolizumab may be referred to as *the study drug*.

Ulcerative colitis (UC) is a condition that affects the large bowel and the
rectum which is the end of the bowel where the stools are stored. The condition
causes the inflammation of the lining of the large bowel and rectum, which can
result in small ulcers developing. Symptoms of UC can include recurring
diarrhoea that may include blood, pain in the stomach, loss of appetite, weight
loss and tiredness.

Crohn*s disease (CD) is a condition that can affect any part of the digestive
system, anywhere from the mouth to the back passage. It commonly affects the
end of the small bowel and start of the large bowel. The condition causes
inflammation of these areas that result in symptoms such as diarrhoea which may
include blood, pain in the stomach, loss of appetite, weight loss, fever and
tiredness. Other problems may also occur as a result of CD such as mouth
ulcers, skin rashes, red and sore eyes and swelling and joint pain.

Primary Objective:
• To determine the safety profile of long-term vedolizumab IV treatment in
pediatric subjects with UC or CD.

Secondary Objectives:
• To determine the effect of long-term vedolizumab IV treatment on time to
major inflammatory bowel disease (IBD)-related events (hospitalizations,
surgeries, and procedures) in pediatric subjects with UC or CD.
• To examine the effect of long-term vedolizumab IV treatment on health-related
quality-of- life measurements in pediatric subjects with UC or CD.
• To determine the effect of long-term vedolizumab IV treatment on patterns of
growth and development in pediatric subjects with UC or CD.

This is a phase 2b, open-label, long-term extension study enrolling male and
female pediatric subjects with ulcerative colitis (UC) or Crohn*s disease (CD)
who initiated vedolizumab intravenous (IV) treatment in the phase 2 Study
MLN0002-2003 between the ages of 2 and 17 years, inclusive. To enter the
open-label extension (OLE) study, subjects will have completed Study
MLN0002-2003 and in the opinion of the investigator are expected to benefit
from continued vedolizumab treatment. The study will evaluate the long-term
safety of vedolizumab administered by IV infusion. The study will also evaluate
the effect of long-term vedolizumab IV treatment on the time to major
IBD-related events (hospitalizations, surgeries, or procedures), health-related
quality-of-life measurements, patterns of growth and development, and
exploratory efficacy measures.

Eligibility will be determined and informed consent/pediatric assent will be
obtained on or after Week 14 of Study MLN0002-2003; relevant assessments from
the Week 22 Visits (and endoscopy at Week 14) of Study MLN0002-2003 will be
used as the predose assessments for this OLE study. Subjects will be
administered vedolizumab IV once every 8 weeks (Q8W) at the dose administered
at Week 14 in Study MLN0002-2003. Subjects who experience disease worsening
while receiving the low dose may be escalated to the high dose at the
investigator*s discretion. After completion of the MLN0002-2003 study, subjects
who have their dose increased based on nonresponse should be dosed based on
weight at the time of nonresponse. Blood samples will be collected every 8
weeks to assess pharmacokinetics (PK); the presence of antivedolizumab
antibodies (AVA) will be assessed every 16 weeks. The study will include an
18-week Follow-up Period (Final Safety Visit) and a long-term follow-up safety
survey by telephone, 6 months after the subject*s last dose of study drug, for
all subjects including those who discontinue the study.

Subjects who weigh >=30 kg will receive vedolizumab IV 300 mg (high dose) or 150
mg (low dose) Q8W.
Subjects who weigh <30 kg will receive vedolizumab IV 200 mg (high dose) or 100
mg (low dose) Q8W.

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; therefore it is important to read the section on pregnancy
carefully, even if the patient is a male.

Vedolizumab side effects
The patient will receive vedolizumab, the study drug. During the study the
patient should not take any other medications without talking to the study
doctor/staff. This includes over the counter medications, herbal preparations
(tablets, capsules, etc.) or vitamins. As of 19 November 2016, more than 4200
adult subjects have received at least 1 dose of vedolizumab in clinical trials
and 1832 subjects have received at least 12 months of vedolizumab exposure. In
intravenous studies to date, vedolizumab has been well tolerated.

The most common side effects from controlled clinical trials, reported in 10%
-20% of adult patients, include:
• worsening of CD in patients with CD
• worsening of UC in patients with UC
• 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.

Risks associated with an endoscopy (flexible sigmoidoscopy or colonoscopy)
An ileocolonoscopy (also called a colonoscopy) or flexible sigmoidoscopy is an
examination that looks at the inside of the colon (large intestine), rectum,
and if an ileocolonoscopy is performed the exam may include the first part of
the small intestine as well as the large intestine and rectum. The examination
uses a tool called a colonoscope or flexible sigmoidoscope. In preparation the
patient will need to completely cleanse your intestines.

The patient will be provided with detailed instructions about the cleansing
preparation, but in general it consists of drinking a large volume of a special
cleansing solution or several days of a clear liquid diet and laxatives or
enemas (fluid injection given through the rectum) prior to the examination.
These instructions should be followed exactly as prescribed or the examination
may be unsatisfactory.

On the day of the examination the patient may be given medicine prior to the
examination to help the patient relax, or given a general anaesthetic; the
patient could have some discomfort during the examination. The patient will lie
on his left side with his knees drawn up toward his chest. The colonoscope or
flexible sigmoidoscope is inserted into the anus and, under visual control, is
gently moved into the rectum and through the colon. Air will be inserted
through the scope to provide a better view and suction may be used to remove
fluid or stool.

The patient may feel pressure as the scope moves inside. Following the
examination, the patient will be kept in an observation area until the effects
of the medications 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.

The following are possible discomforts or risks associated with a colonoscopy:
• Heavy or ongoing bleeding from biopsy or removal of polyp
• Cramping, pain, 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
preparation
• Side effects, like drowsiness following sedative or pain medication

Risks associated with infusion site reactions (IV administration)
An infusion site reaction is a localized reaction that may occur along the vein
or surrounding area where the medication is injected. 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. The patient should tell the study
doctor/staff right away if the patient experiences any problems at the infusion
site.

Risks associated with Electrocardiograms (ECGs)
An electrocardiogram (ECG) is a test that tells how the heart is working. The
patient will have small, soft pads, placed temporarily on different parts of
your body. 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
During the collection of blood samples, the patient may experience pain and/or
bruising at the needle injection site. 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.

Vedolizumab side effects
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. It is not known if
the side effects seen in adults will be similar to those seen in children.

In addition to the risks listed above, vedolizumab and study procedures may
have unknown risks. There is always the possibility that the patient will have
a side effect that is currently unknown or not expected. It is important that
the patient will report any and all symptoms/health problems to the study
doctor/staff, whether or not they think these problems are related to the study
drug. The patient will be monitored for side effects and the study doctor may
decide that the patient should be withdrawn from the study for the patient's
safety.

As with any drug, allergic reactions may occur. If the patient has a very bad
allergic reaction, the patient 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

The study doctor/staff should be notified immediately if the patient has these
or any other side effects during the study. The study doctor and team will be
prepared to treat the patient if the patient has an allergic reaction.

There is possibility of a greater chance of getting an infection, difficulty
fighting off an infection, or reactivation of an old infection. Serious
infections have occurred. The patient will be monitored for infections and
treated as needed. Please tell the patient's study doctor if the patient
currently has, or has recently had, any of the following signs and/or symptoms
which could be due to a serious infection:
• A sudden change in level of consciousness
• High or low temperature (>38.5 or <36°C)
• Fast heart beat
• Difficult or fast breathing
• Passing out or feeling faint
• Drowsiness or are difficult to wake up
• Unusual irritability
• Poor eating or drinking
• Seizure (fits)
• Sudden or dramatic increase in pain

There is a possibility that treatment with vedolizumab could cause reactivation
of an old infection such as TB. The study doctor must be told if the patient
has ever had or been treated for TB. Patients with long standing inflammation
of the colon due to UC or CD 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.

As mentioned above, no cases of Progressive Multifocal Leukoencephalopathy
(PML) 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. PML is caused by a virus called JCV (John
Cunningham virus) that can infect the brain. Many people carry the virus but do
not get sick from PML. When PML does occur, it is usually in people who have a
weakened immune system and a decreased ability to fight off infection. PML
usually causes death or severe disability. There is no proven treatment,
prevention or cure for PML. During this study the patient will be monitored to
see if you have any symptoms of PML. The patient will be instructed about the
symptoms of PML. If the patient has any one of these symptoms, they must be
reported to the study doctor immediately. The study doctor will be prepared to
test the patient and send the patient to a specialist for further tests if
needed. The specialist may order a brain scan called an MRI and may perform a
spinal tap.

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 and were not felt to be
due to vedolizumab. No changes in monitoring of the trials were recommended by
the Board.