A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Study of SHP647 as Induction Therapy in Subjects With Moderate to Severe Crohn*s Disease (CARMEN CD 305)

1.Subjects and/or their parent or legally authorized representative must have
an understanding, ability, and willingness to fully comply with study
procedures and restrictions.
2.Subjects must be able to voluntarily provide written, signed, and dated
(personally or via a legally authorized representative) informed consent and/or
assent as applicable to participate in the study.
3.Subjects must be between *16 and *80 years of age at the time of the signing
of the informed consent/assent form. Note: Subjects <18 years of age must weigh
*40 kg and must have body mass index *16.5 kg/m2.
4.Subjects must have active moderate to severe ileal (terminal ileum),
ileocolic, or colonic CD at baseline (Visit 2) as defined by:
a.CDAI score between 220 and 450 (inclusive) AND
b.Presence of ulcerations that are characteristic to CD, as determined by a
colonoscopy performed during screening, and as defined by the SES-CD
>6 (SES-CD *4 for isolated ileitis) AND
c.Meeting the following subscores in the 2-item PRO:
i.Abdominal pain subscore *5 (average worst daily pain on the 11-point NRS) AND
abdominal pain subscore >2 (average daily pain on the 4-point abdominal pain
variable of CDAI) over the 7 most recent days out of the 10 days before
colonoscopy preparation (may or may not be contiguous) AND/OR
ii.Average of the daily stool frequency subscore *4 of type 6/7 (very soft
stools/liquid stools) as shown in the BSFS over the 7 most recent days out of
the 10 days before colonoscopy preparation (may or may not be contiguous).
AND
c. Presence of ulcerations that are characteristic to CD, as determined by a
colonoscopy performed during screening, and as defined by the SES-CD>6 (SES-CD
*4 for isolated ileitis)
Note that the subject must be confirmed as meeting the CDAI score and PRO
subscore requirements before a colonoscopy is done.
5.Subjects must have a documented diagnosis (endoscopic with histology) of CD
for *3 months before screening. Documented diagnosisis defined as:
A biopsy report in which the description of the histological findings is
consistent with the CD diagnosis AND
A report documenting disease duration based upon prior colonoscopy.
Note: If a biopsy report is not available in the source document at the time of
screening, a biopsy must be performed during the screening colonoscopy and the
histology report should be consistent with the CD diagnosis. If the histology
diagnosis does not support the CD diagnosis at this time point, the subject
should not be randomized
6.Subjects must be willing and able to undergo a colonoscopy during screening
after all other inclusion criteria have been met.
7.Subjects must have had an inadequate response to, or lost response to, or had
an intolerance to at least 1 conventional treatment such as sulfasalazine or
mesalamine (5-ASA), glucocorticoids, immunosuppressants (AZA, 6-MP, or MTX), or
anti-TNF. Subjects who have had an inadequate response to sulfasalazine or
mesalamine should have also failed at least 1 other conventional treatment such
as glucocorticoids.
8.Subjects receiving any treatment(s) for CD described in Section 5.2.1 of the
protocol are eligible provided they have been, and are anticipated to be, on a
stable dose for the designated period of time.
9. Subjects are males or nonpregnant, nonlactating females who, if sexually
active, agree to comply with the contraceptive requirements of the protocol, or
females of nonchildbearing potential. Males and females of reproductive
potential who are sexually active must agree to use appropriate contraception
(ie, highly effective methods for female and medically appropriate methods for
male study subjects) (as described in Section 4.4) for the duration of the
study.

Subjects are excluded from the study if any of the following exclusion criteria
are met.
1.Subjects with indeterminate colitis, microscopic colitis, non-steroidal
anti-inflammatory drug-induced colitis, ischemic colitis, infectious colitis,
or clinical/histologic findings suggestive of ulcerative colitis.
2. Subjects with colonic dysplasia or neoplasia. (Subjects with prior history
of adenomatous polyps will be eligible if the polyps have been completely
removed.)
3. Subjects with past medical history or presence of toxic megacolon.
4. Subjects with presence of enterovesical (ie, between the bowel and urinary
bladder) or enterovaginal fistulae.
5. Subjects with current symptomatic diverticulitis or diverticulosis.
6. Subjects with clinically significant obstructive colonic stricture, or who
have a history of bowel surgery within 6 months before screening, or who are
likely to require surgery for CD during the treatment period. Subjects who have
undergone previous colonic resection or ileocolectomy more than 6 months before
screening must have at least 25 cm of colon remaining.
7. Subjects with past medical history of multiple small bowel resections
resulting in clinically significant short bowel syndrome.
8. Subjects requiring total parenteral nutrition.
9. Subjects with past medical history of bowel surgery resulting in an existing
or current stoma. Subjects who had a j-pouch are excluded as a j-pouch could
result in a stoma.
10. Subjects have had prior treatment with ontamalimab (formerly PF-00547659;
SHP647).
11. Subjects with known or suspected intolerance or hypersensitivity to the
investigational product(s), closely related compounds, or any of the stated
ingredients.
12. Subjects have received any nonbiologic treatment with immunomodulatory
properties (other than AZA, 6 MP, or MTX) or continuous antibiotics (>2 weeks)
for the treatment of CD within 30 days before baseline (Visit 2).
13. Subjects have received anti-TNF treatment within 60 days before baseline
(Visit 2).
14. Subjects have received any biologic with immunomodulatory properties (other
than anti TNFs) within 90 days before baseline (Visit 2).
15. Subjects have ever received anti-integrin/adhesion molecule treatment (eg,
natalizumab, vedolizumab, efalizumab, etrolizumab, or any other investigational
anti-integrin/adhesion molecule).
16. Subjects have received lymphocytes apheresis or selective monocyte
granulocytes apheresis within 60 days before baseline (Visit 2).
17. Subjects have received enteral nutrition treatment within 30 days before
baseline (Visit 2).
18. Subjects have received parenteral or rectal glucocorticoids or rectal 5-ASA
within 14 days before screening colonoscopy.
19. Subjects have taken >20 mg/day of prednisone, >9 mg/day of budesonide, or
equivalent oral systemic corticosteroid dose within 14 days before baseline
(Visit 2) or have taken *40 mg/day of prednisone or equivalent oral systemic
corticosteroid dose within 6 weeks before baseline (Visit 2).
20. Subjects have participated in other investigational studies within either
30 days or 5 half lives of investigational product used in the study (whichever
is longer) before screening (Visit 1).
21. Subjects have received a live (attenuated) vaccine within 30 days before
the baseline visit (Visit 2).
22. Subjects with active enteric infections (positive stool culture and
sensitivity), Clostridium difficile infection or pseudomembranous colitis
[subjects with C. difficile infection at screening may be allowed retest after
treatment], evidence of active cytomegalovirus infection or Listeria
monocytogenes, known active invasive fungal infections such as histoplasmosis
or parasitic infections, clinically significant underlying disease that could
predispose the subjects to infections, or a history of serious infection
(requiring parenteral antibiotic and/or hospitalization) within 4 weeks before
the baseline visit (Visit 2).
23. Subjects with abnormal chest x-ray or other imaging findings at screening
(Visit 1), such as presence of active tuberculosis (TB), general infections,
heart failure, or malignancy. (A chest x ray, computed tomography scan, etc.,
performed up to 12 weeks before study entry [screening, Visit 1] may be used if
available; documentation of the official reading must be located and available
in the source documentation.)
24. Subjects with evidence of active or latent infection with Mycobacterium
tuberculosis (TB) or subjects with this history who have not completed a
generally accepted full course of treatment before baseline (Visit 2) are
excluded. All other subjects must have either the Mantoux (purified protein
derivative [PPD]) tuberculin skin test or interferon-gamma release assay (IGRA)
performed.
Subjects who have no history of previously diagnosed active or latent
tuberculosis are excluded if they have a positive Mantoux (PPD) tuberculin skin
test (ie *5 mm induration) or a positive IGRA (the latter to be tested at the
site*s local laboratory) during screening or within 12 weeks before screening.
If the IGRA cannot be performed locally, a central laboratory may be used, with
prior agreement from the sponsor.
* An IGRA is strongly recommended for subjects with a prior bacillus Calmette
Guérin vaccination, but may be used for any subject. Documentation of IGRA
product used and the test result must be in the subject's source documentation
if performed locally. Acceptable IGRA products include QuantiFERON-TB Gold Plus
In-Tube Test.
* If the results of the IGRA are indeterminate, the test may be repeated, and
if a negative result is obtained, enrollment may proceed. In subjects with no
history of treated active or latent TB, a positive test on repeat will exclude
the subject. Subjects with a history of active or latent TBinfection must
follow instructions for *Subjects with a prior diagnosis of active or latent TB
are excluded unless both of the following criteria are met* in this criterion.
* Subjects with repeat indeterminate IGRA results, with no prior TB history,
may be enrolled after consultation with a pulmonary or infectious disease
specialist who determines low risk of infection (ie, subject would be
acceptable for immunosuppressant [eg, anti-TNF] treatment without additional
action). This consultation must be included in source documentation.
Results from a chest x-ray, taken within the 12 weeks before or during
screening (Visit 1) must show no abnormalities suggestive of active TB
infection as determined by a qualified medical specialist.
Subjects with a prior diagnosis of active or latent tuberculosis are excluded
unless both of the following criteria are met:
* The subject has previously received an adequate course of treatment for
either latent (eg, 9 months of isoniazid or an acceptable alternative regimen,
in a locale where rates of primary multidrug TB resistance are <5%. Subjects
from regions with higher rates of primary multidrug TB resistance are excluded)
or active (acceptable multidrug regimen) TB infection. Evidence of diagnosis
and treatment must be included in source documentation. Consultation with a
pulmonary or infectious disease specialist to confirm adequate treatment (ie,
subject would be acceptable for immunosuppressant [eg, anti TNF] treatment
without additional action) must be performed during the screening period. The
consultation report must be included in source documentation prior to
enrollment.
* A chest x-ray performed within 12 weeks before screening (Visit 1) or during
screening (Visit 1) indicates no evidence of active or recurrent disease, and
documentation of interpretation by a qualified medical specialist must be
included in source documentation.
25. Subjects with a pre existing demyelinating disorder such as multiple
sclerosis or new onset seizures, unexplained sensory motor, or cognitive
behavioral, neurological deficits, or significant abnormalities noted during
s