An Active Treatment Study to Induce Clinical Response and/or Remission With GSK1605786A in Subjects With Crohn's Disease

This is a multi-centre, double-blind, randomised, active treatment, parallel group study
designed to induce clinical response and/or clinical remission with two oral doses of
GSK1605786A (500 milligrams once daily, 500 milligrams twice daily) over a 12-week treatment
period in subjects with moderately-to-severely active Crohn's disease. The primary objective
of this study is to qualify subjects for enrolment into a follow up 52 week maintenance study
CCX114157. Subjects who achieve induction of clinical response (CDAI decrease from baseline
of at least 100 points) or remission (CDAI score less than 150) at Week 12 following
treatment with GSK1605786A will be eligible for enrolment into the maintenance study
CCX114157. Secondary objectives will include assessment of the safety and evaluation of the
efficacy in induction of clinical response or remission.

The study is planned to randomise approximately 900 subjects (450 subjects per group) with
active Crohn's disease who have been diagnosed for at least 4 months, with documented history
of disease in the small and/or large intestine, and characterised by a CDAI score between 220
to 450 (inclusive). Subjects will be required to have evidence of current active inflammation
by elevated C-reactive protein (greater than the upper limit of normal of the highly
sensitive C-reactive protein test) OR an elevated level of faecal calprotectin. Subjects will
be allowed to participate in the study while continuing on stable doses of agents typically
used to treat Crohn's disease. Inclusion of subjects who received prior treatment with an
anti-tumor necrosis factor agent and discontinued due to loss or lack of efficacy will be
limited to approximately 50 percent of the study population. Following a 3-week screening
period, subjects will be randomised at baseline to receive blinded treatment with one of two
doses of GSK1605786A (500 milligrams once daily or twice daily) for 12 weeks. All subjects
meeting the definition of responder (CDAI decrease from baseline of at least 100 points) or
who are in remission (CDAI score less than 150 points) at Week 12 will be eligible for
randomisation into an ongoing maintenance study (CCX114157). Subjects who do not meet the
definition of responder or who are not in remission at Week 12 will not be eligible to
participate in study CCX114157.

For subjects who complete the study the minimum duration of participation is 15 weeks and the
maximum duration is 19 weeks.

Inclusion Criteria:

- Male or female subjects aged 18 years or older

- Written informed consent prior to any of the screening procedures including
discontinuation of prohibited medications

- Diagnosis of Crohn's disease for more than 4 months with small bowel and/or colonic
involvement

- Current evidence of moderately-to-severely active disease defined by a baseline
Crohn's Disease Activity Index (CDAI) score of 220 to 450, inclusive

- Confirmation of active disease by elevated CRP (greater than or equal to the upper
limit of normal for the highly sensitive C-reactive protein test) or elevated levels
of faecal calprotectin

- History of inadequate response and/or intolerance or adverse event leading to
discontinuation of at least one of the following treatments for Crohn's disease:
corticosteroids or immunosuppressants

- Stable doses of permitted concomitant medications or having previously received, but
are not currently receiving, medications for Crohn's disease

- Demonstrated ability to comply with Crohn's disease symptom recording using the
interactive voice response system

- Female subjects of child-bearing potential are eligible if not pregnant or nursing and
committed to use of contraceptive methods with a failure rate of less than 1 percent
per year

Exclusion Criteria:

- Known coeliac disease, those who follow a gluten-free diet to manage symptoms of
suspected coeliac disease and subjects with a positive screening test for coeliac
disease (elevated anti-tissue transglutaminase antibodies)

- Diagnosis of ulcerative or indeterminate colitis

- Enterocutaneous, abdominal or pelvic fistulae with abscesses, or fistulae likely to
require surgery during the course of the study period

- Bowel surgery, other than appendectomy, within 12 weeks prior to screening and/or has
planned surgery or deemed likely to need surgery for Crohn's disease during the study
period

- Extensive colonic resection, subtotal or total colectomy

- Presence of ileostomies, colostomies or rectal pouches

- Fixed symptomatic stenoses of small bowel or colon

- History of more than 3 small bowel resections or diagnosis of short bowel syndrome

- Chronic use of narcotics for chronic pain defined as daily use of one or more doses of
narcotic containing medicaitons

- Use of prohibited medications, including enteral feeding or elemental diet, within
their specified timeframes and throughout the study. Prohibited medications include
the following:

1. Biologic use: Use of any TNF inhibitor (such as infliximab, adalimumab or
certolizumab) or natalizumab within 10 weeks prior to Randomisation

2. Corticosteroid use: Use of parenteral glucocorticoids within 4 weeks prior to
Screening

3. Immunospressant use: Use of cyclosporine, tacrolimus, sirolimus or mycophenolate
mofetil within 4 weeks prior to Screening

4. Intravenous antibiotic use: Use of intravenous antibiotics for Crohn's disease
within 4 weeks prior to Screening

5. Enteral feeding: Use of tube or enteral feeding, elemental diet within 2 weeks
prior to Screening

6. Rectal Treatment: Use of 5-aminosalicylates or corticosteroid enemas or
suppositories within 2 weeks prior to Screening

7. Leukocytapheresis or granulocytapheresis within 2 weeks prior to Screening

8. Paracetamol or acetaminophen greater than 2 grams per day

9. Opioid analgesics for worsening Crohn's disease pain are prohibited when used on
a regular daily basis for more than 3 days

10. Digoxin or related cardiac glycosides: Use within 7 days prior to Screening

11. Any previous participation in a clinical study of GSK1605786A (formerly
ChemoCentryx compound CCX282-B)

- Positive immunoassay for Clostridium difficile

- Known HIV infection

- Known varicella, herpes zoster, or other severe viral infection within 6 weeks of
screening

- Immunization with a live vaccine within 4 weeks of Screening and throughout the study
with the exception of the influenza vaccine

- Positive hepatitis B surface antigen or hepatitis B core antibody test or positive
Hepatitis C test result at Screening

- Active or latent tuberculosis infection determined by results of QuantiFERON TB Gold
test

- Current sepsis or infections requiring intravenous antibiotic therapy for more than 2
weeks

- Previous infections characterised by opportunistic pathogens, and/or dissemination
suggestive of clinically significant immunocompromise

- Evidence of hepatic dysfunction, viral hepatitis, or abnormalities in liver function
test results

- Corrected QT interval of ECG (electrocardiogram) greater than or equal to 450
milliseconds

- Congenital or acquired immunodeficiency or has evidence of immunocompromise manifested
by current opportunistic infection

- Current evidence of, or has been treated for a malignancy within the past five years
(other than localised basal cell, squamous cell skin cancer, cervical dysplasia, or
any cancer in situ that has been resected)

- History of evidence of adenomatous colonic polyps that have not been removed.

- History of evidence of colonic mucosal dysplasia

- If female, is pregnant, has a positive pregnancy test or is breast-feeding

- Concurrent illness or disability that may affect the interpretation of clinical data,
or otherwise contraindicates participation in this clinical study (such as an unstable
cardiovascular, autoimmune, renal, hepatic, pulmonary, endocrine, metabolic,
gastrointestinal, haematologic, or neurological condition or mental impairment)

- Medical history of sensitivity to any of the components of GSK1605786A
(microcrystalline cellulose, crospovidone, sodium stearyl fumarate).

- Use of any investigational product within 30 days prior to screening