A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Efficacy of AMG 181 in Subjects with Moderate to Severe Crohn*s Disease

Inflammatory bowel disease (IBD) affects approximately 1.4 million people in
the US and 2.2 million people in Europe. The peak onset is between 15 and 30
years of age (Loftus and Sandborn, 2002). IBD comprises 2 types of chronic
intestinal disorders: CD and ulcerative colitis (UC). Accumulating evidence
suggests that IBD results from an inappropriate inflammatory response to
intestinal microbes in a genetically susceptible host (Abraham and Cho, 2009).
Treatment of IBD includes lifestyle alterations, medical management, and
surgical interventions. The overarching goals of medical management are: first,
to induce disease remission and, second, to ensure that this remission is
sustained over long periods of time. Medical management of IBD patients
typically uses a step-up approach (Devlin and Panaccione, 2010). The standard
therapies available for CD include 5-aminosalicylates, antimicrobial therapy,
corticosteroids, immunosuppressive agents, and monoclonal antibodies. In the US
there are currently 4 biologic agents marketed for use in Crohn*s disease.
Three are in the anti-TNF (Tumor Necrosis Factor) class: infliximab (Remicade®,
administered intravenously [IV]), adalimumab (Humira®, administered SC), and
certolizumab pegol (Cimzia®, administered SC). The fourth one, natalizumab
(Tysabri®, administered IV), is an anti-trafficking agent targeting the *4
integrin chain and thereby binding to both the *4*1 and *4*7 heterodimeric
receptors. In the EU, infliximab and adalimumab are the only biological agents
commercialized for use in Crohn*s disease. Induction therapy for patients with
mild-to-moderate CD typically uses 5-aminosalicylates or antimicrobial agents.
The immunosuppressive agents azathioprine (AZA), 6-mercaptopurine (6-MP), and
methotrexate (MTX) can also be used to induce remission, yet are typically
slow-acting and require concomitant administration of corticosteroids. Failure
to induce remission with the aforementioned agents, or more severe forms of the
disease, will lead to the use of high dose corticosteroids or monoclonal
antibodies as induction therapy. Only the immunosuppressive agents (AZA, 6-MP,
and MTX) and biologic agents have documented efficacy in the maintenance of
response and remission in CD. Because of therapeutic failures and serious side
effects of present therapies, additional treatment alternatives are needed.

AMG 181 is a fully human monoclonal immunoglobulin IgG2 antibody that
specifically recognizes the human *4*7integrin heterodimer. AMG 181 binds *4*7
with high affinity and blocks its interaction with MAdCAM 1. Refer to the AMG
181 investigator*s brochure for additional information.
No serious adverse events considered by the investigator to be related to AMG
181 have been reported through 3 January 2012. No anti AMG 181 antibodies have
been detected from serum samples collected thus far from healthy subjects.
Refer to the AMG 181 investigator*s brochure for additional information.

To evaluate the efficacy of AMG 181 as measured by the proportion of subjects
achieving Crohn*s Disease Activity Index (CDAI) remission (CDAI < 150) at week
8.

This is a randomized, double-blind, placebo-controlled, parallel group,
multiple dose study to evaluate the efficacy of AMG 181 compared with placebo
as measured by the proportion of subjects in remission (CDAI score < 150) at
week 8. After completing all screening assessments and meeting all eligibility
criteria, subjects will be randomized in a 2:1:2:1 ratio to receive placebo or
AMG 181 21 mg, 70 mg or 210 m (randomization will be stratified by prior
anti-TNF use and participation in the pharmacokinetics [PK] substudy). At the
end of the double-blind period (week 24), subjects will enter a 108-week
open-label period during which all subjects will receive open-label 210 mg AMG
181 every 3 months. Subjects who fail to achieve minimal improvement, or
experience disease worsening after initial response (criteria defined in
Section 3.1.2.1), are eligible to enter the open-label period early beginning
at week 12 or after. All subjects must withdraw immunomodulators (azathioprine,
6-mercaptopurine, methotrexate) at week 8. Corticosteroid tapering will be
mandated for patients in remission as described in Section 6.3. Subjects will
enter a 2-year safety follow-up period starting from the last dose of
double-blind investigational product or last dose of open-label AMG 181
(whichever comes later). Disease remission (defined as a CDAI score < 150) and
disease response (defined as either remission or a reduction of the CDAI score
with * 100 points) will be assessed at all visits.
Prior to entry into the open-label period, subjects will complete the
procedures of the week 24/end of double-blind visit and the open-label baseline
visit as described in Section 3.1.2.1 of the protocol. Subjects who have
achieved response at week 8 and subsequently experience disease worsening are
eligible to enter the open-label period early beginning at week 12 or after as
described in Section 3.1.2.1 of the protocol. At the open-label week 12 visit,
withdrawal of open-label AMG 181 and completion of an early termination (ET)
visit is recommended for subjects with a CDAI score > 250, unless they have a
decrease of * 70 points from either the baseline CDAI score or the week 24/End
of Double-Blind CDAI score, whichever was higher. In addition, for subjects
experiencing recurrence of significant CD symptoms as per investigator judgment
at any time during the open-label period, withdrawal of open-label AMG 181 and
completion of an early termination (ET) visit is recommended.
A safety follow-up interview (in person or by phone) to assess for symptoms of
PML will be conducted at approximately 3, 6, 12, 18, and 24 months after the
last dose of open-label AMG 181 (ie, open-label week 96 visit). For subjects
that early terminate from the study and agree to the safety follow-up period,
phone calls will be conducted at the same frequency, but scheduled based on the
subject*s last dose of double-blind investigational product or last dose of
open-label AMG 181, whichever comes later. Any new, clinically significant,
unexplained neurological symptom will mandate evaluation by a neurologist
consultant. An independent committee with expertise in neurological
manifestations of PML will review clinical data and may apply a pre-specified
diagnostic algorithm for PML (see Sections 2.4.2 and 7.1.6 in the protocol).
Subjects with abnormal hepatic laboratory values (eg, ALP, AST, ALT, total
bilirubin) or signs/symptoms of hepatitis may meet the criteria for withholding
of investigational product. Withholding is either permanent or conditional
depending upon the clinical circumstances. Criteria for permanent or
conditional withholding investigational product in the event that a subject
develops signs or symptoms of hepatitis during a clinical trial is provided in
Appendix C.
In the event that a subject receives a treatment listed in Section 6.4 of the
protocol, investigational product must be withdrawn and the subject must
complete an early termination visit.
A maximum of approximately 80% of subjects with any prior anti-TNF agent use
will be allowed in the study. If approximately 80 % of the aimed number of
randomized patients who haved used an anti-TNF drug has been randomized, only
subjects who are anti-TNF naif and have used an immunomodulator will be allowed
in the study.

-Completion of Patient Reported Outcomes and a patient diary
-SC injections with the asigned study medication (AMG 181 or placebo)
-Blood en urine collections
-ECGs
-Physical examination
-Chest X-ray (if applicable)
-Brain MRI (if applicable)
-Lumbar punction (if applicable)
-Brain biopsy (if applicable)
-Tuberculosis test (PPD or quantiferon; if applicable)
-Collection stool samples

Patients may not use specific treatments during the study (from screening until
the end of the open label period). See protocol page 41, section 6.4 ("Excluded
Treatments During the Study Period").

Risks: side effects from the study drug.

Burden:
-Additional visit as described in question E2
-Physical examination
-Blood collections
-Urine collectoions
-ECG's
-Patiënten Reported Outcomes
-Completing patient diary
-SC injections with AMG 181 and/or placebo
-Optional PK study (additional blood collections)
-Chest X-ray (if applicable)
-Brain MRI (if applicable)
-Lumbar punction (if applicable)
-Brain biopsy (if applicable)
-Tuberculosis test (PPD or quantiferon; if applicable)
-Collection stool samples
-Optional Biomarker blood- and stool samples sub study (additional blood
samples)
-Optional White Blood Cell Type Testing (additional blood samples)

Patients may not use specific treatments during the study (from screening until
the end of the open label period). See protocol page 41, section 6.4 ("Excluded
Treatments During the Study Period").

Risks:
See answer question E9.