A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by MLN0002 in Patients with Moderate to Severe Ulcerative Colitis

Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Age 18 to 80
2. Male or female patient who is voluntarily able to give informed consent
3. Female patients who:
* Are post-menopausal for at least 1 year before the screening visit, OR
* Are surgically sterile, OR
* If they are of childbearing potential, agree to practice 2 effective methods of
contraception, at the same time, from four weeks before the first dose of
study drug through 6 months after the last dose of study drug, OR agree to
completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status post-vasectomy), who:
* Agree to practice effective barrier contraception during the entire study
treatment period and through 6 months after the last dose of study drug, OR
* Agree to completely abstain from heterosexual intercourse.
4. Diagnosis of ulcerative colitis established at least 6 months prior to enrollment
by clinical and endoscopic evidence and corroborated by a histopathology
report.
5. Moderately to severely active ulcerative colitis as determined by a Mayo score
of 6 to 12 with an endoscopic subscore *2 within 7 days prior to the first dose
of study drug (see Section 15.1)
6. Evidence of ulcerative colitis extending proximal to the rectum (*15 cm of
involved colon)
7. Patients with extensive colitis or pancolitis of >8 years duration or left-sided
colitis of >12 years duration must have documented evidence that a
surveillance colonoscopy was performed within 12 months of the initial
screening visit (may be performed during screening).
8. Patients with a family history of colorectal cancer, personal history of
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increased colorectal cancer risk, age >50 years, or other known risk factor must
be up-to-date on colorectal cancer surveillance (may be performed during
screening)
9. Demonstrated, over the previous 5 year period, an inadequate response to, loss
of response to, or intolerance of at least one of the following agents as defined
below:
* Corticosteroids
o Signs and symptoms of persistently active disease despite a history of at
least one 4-week induction regimen that included a dose equivalent to
prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week OR
o Two failed attempts to taper corticosteroids to below a dose equivalent to
prednisone 10 mg daily orally OR
o History of intolerance of corticosteroids (including, but not limited to
Cushing*s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia,
infection)
* Immunomodulators
o Signs and symptoms of persistently active disease despite a history of at
least one 8 week regimen of oral azathioprine (*1.5 mg/kg) or 6-
mercaptopurine mg/kg (*0.75 mg/kg) OR
o History of intolerance of at least one immunomodulator (including, but not
limited to nausea/vomiting, abdominal pain, pancreatitis, LFT
abnormalities, lymphopenia, TPMT genetic mutation, infection)
* TNF* antagonists
o Signs and symptoms of persistently active disease despite a history of at
least one 4 week induction regimen of infliximab 5 mg/kg IV, 2 doses at
least 2 weeks apart OR
o Recurrence of symptoms during maintenance dosing following prior
clinical benefit (discontinuation despite clinical benefit does not qualify)
OR
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o History of intolerance of infliximab (including, but not limited to infusionrelated
reaction, demyelination, congestive heart failure, infection)
10. May be receiving a therapeutic dose of the following drugs:
a. Oral 5-ASA compounds provided that the dose has been stable for the
2 weeks immediately prior to enrollment
b. Oral corticosteroid therapy (prednisone at a stable dose *30 mg/day, or
equivalent steroid) provided that the dose has been stable for the 4 weeks
immediately prior to enrollment if corticosteroids have just been initiated, or
for the 2 weeks immediately prior to enrollment if corticosteroids are being
tapered
c. Probiotics (eg, Culturelle, Saccharomyces boulardii) provided that the dose
has been stable for the 2 weeks immediately prior to enrollment
d. Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of
chronic diarrhea
e. Azathioprine or 6-mercaptopurine provided that the dose has been stable for
the 8 weeks immediately prior to enrollment

Exclusion Criteria
The exclusion criteria are divided into 3 categories: gastrointestinal exclusion criteria,
infectious disease exclusion criteria, and general exclusion criteria. Patients meeting any of
the following exclusion criteria are not to be enrolled in the study.
5.2.1 Gastrointestinal Exclusion Criteria
1. Evidence of abdominal abscess or toxic megacolon at the initial screening visit
2. Extensive colonic resection, subtotal or total colectomy
3. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
4. Within 30 days prior to enrollment, have received any of the following for the
treatment of underlying disease:
a. Non-biologic therapies (eg, cyclosporine, thalidomide) other than those
permitted in Section 6.2
b. A non-biologic investigational therapy
c. An approved non-biologic therapy in an investigational protocol
5. Within 90 days prior to enrollment, have received any of the following:
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a. Infliximab
b. Other investigational or approved biologic agent
6. Any prior exposure to natalizumab or rituximab
7. Use of topical (rectal) treatment with 5-ASA or corticosteroid
enemas/suppositories within 2 weeks of the administration of the first dose of
study drug
8. Evidence of or treatment for C. difficile infection within 60 days or other
intestinal pathogen within 30 days prior to enrollment
9. Currently require or are anticipated to require surgical intervention for UC
during the study
10. History or evidence of adenomatous colonic polyps that have not been
removed
11. History or evidence of colonic mucosal dysplasia
12. Diagnosis of Crohn*s colitis or indeterminate colitis
5.2.2 Infectious Disease Exclusion Criteria
1. Chronic hepatitis B or C infection
2. Active or latent tuberculosis, regardless of treatment history, as evidenced by
any of the following:
a. History of tuberculosis
b. A positive diagnostic tuberculosis (TB) test within one month of
enrollment defined as:
i. a positive QuantiFERON® test or 2 successive indeterminate
QuantiFERON® tests OR
ii. a tuberculin skin test reaction *10 mm ( *5 mm in patients receiving
the equivalent of > 15 mg/day prednisone).
c. Chest X-ray within 3 months of enrollment in which active or latent
pulmonary tuberculosis cannot be excluded
3. Any identified congenital or acquired immunodeficiency (eg, common variable
immunodeficiency, human immunodeficiency virus [HIV] infection, organ
transplantation)
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4. Any live vaccinations within 30 days prior to study drug administration except
for the influenza vaccine
5. Clinically significant extra-intestinal infection (eg, pneumonia, pyelonephritis)
within 30 days prior to enrollment
5.2.3 General Exclusion Criteria
1. Previous exposure to MLN0002
2. Female patients who are lactating or have a positive serum pregnancy test
during the screening period or a positive urine pregnancy test on Day 1 prior to
study drug administration.
3. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal,
gastrointestinal, genitourinary, hematological, coagulation, immunological,
endocrine/metabolic, or other medical disorder that, in the opinion of the
investigator, would confound the study results or compromise patient safety
4. Had any surgical procedure requiring general anesthesia within 30 days prior
to enrollment or is planning to undergo major surgery during the study period
5. Any history of malignancy, except for the following: (a) adequately-treated
non-metastatic basal cell skin cancer; (b) any other type of non-melanoma skin
cancer that has been adequately treated and has not recurred for at least 1 year
prior to enrollment; and (c) adequately treated in situ cervical cancer that has
not recurred for at least 1 year prior to enrollment
6. History of any major neurological disorders, including stroke, multiple
sclerosis, brain tumor, or neurodegenerative disease
7. Positive PML subjective symptom checklist prior to the administration of the
first dose of study drug
8. Any of the following laboratory abnormalities during the screening period:
a. Hemoglobin level <8 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
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e. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
>3 × the upper limit of normal (ULN)
f. Alkaline phosphatase >3 × ULN
g. Serum creatinine >2 × ULN
9. Current or recent history (within one year prior to enrollment) of alcohol
dependence or illicit drug use
10. Active psychiatric problems that, in the investigator*s opinion, may interfere
with compliance with the study procedures
11. Unable to attend all the study visits or comply with study procedures