An Active Treatment Study to Induce Clinical Response and/or Remission With GSK1605786A in Subjects With Crohn's Disease
Condition: Crohn's Disease
MeSH terms: Crohn Disease
Intervention: GSK1605786A; GSK1605786A
Intervention description: 500 milligrams once daily, orally administered for 12 weeks; 500 milligrams twice daily, orally adminstered for 12 weeks
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 255.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Crohn's disease, chemokine receptor 9 antagonist, Crohn's Disease Activity Index; active treatment

Summary:

      This is a multi-centre, randomised, double-blind, active treatment, parallel group induction
      study in subjects with moderately-to-severely active Crohn's disease. Subjects will receive
      one of two doses (500 milligrams once daily, 500 milligrams twice daily) of GSK1605786A for
      12 weeks. The primary objective of the study is to induce clinical response (Crohn's Disease
      Activity Index [CDAI] decrease from baseline of at least 100 points) and/or remission (CDAI
      score less than 150) with GSK1605786A at Week 12 in subjects with active Crohn's disease to
      qualify subjects for enrolment into a 52 week maintenance study (CCX114157). Secondary
      objectives will include assessment of the safety and evaluation of the efficacy in induction
      of clinical response or remission. Safety will be assessed by recording of adverse events and
      assessment of changes in clinical laboratory parameters, vital signs and electrocardiogram.
      Population pharmacokinetics will evaluate the two doses of GSK1605786A. Health outcomes
      assessments will include changes in Inflammatory Bowel Disease Questionnaire, SF-36, EQ-5D,
      and Work Productivity and Activity Impairment-Crohn's Disease.
    

Eligibility criteria:

        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