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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomised, Double-blind, Active Treatment Study to Induce Clinical Response and/or Remission With GSK1605786A in Subjects With Moderately-to-Severely Active Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: GSK1605786A
* Drug: GSK1605786A


Participation Criteria
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Eligibility Criteria
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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: Biologic use: Use of any TNF inhibitor (such as infliximab, adalimumab or certolizumab) or natalizumab within 10 weeks prior to Randomisation Corticosteroid use: Use of parenteral glucocorticoids within 4 weeks prior to Screening Immunospressant use: Use of cyclosporine, tacrolimus, sirolimus or mycophenolate mofetil within 4 weeks prior to Screening Intravenous antibiotic use: Use of intravenous antibiotics for Crohn's disease within 4 weeks prior to Screening Enteral feeding: Use of tube or enteral feeding, elemental diet within 2 weeks prior to Screening Rectal Treatment: Use of 5-aminosalicylates or corticosteroid enemas or suppositories within 2 weeks prior to Screening Leukocytapheresis or granulocytapheresis within 2 weeks prior to Screening Paracetamol or acetaminophen greater than 2 grams per day Opioid analgesics for worsening Crohn's disease pain are prohibited when used on a regular daily basis for more than 3 days Digoxin or related cardiac glycosides: Use within 7 days prior to Screening 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK1605786A, 500 milligrams, once daily<br>500 milligrams once daily, orally administered for 12 weeks | Drug: GSK1605786A<br>* 500 milligrams once daily, orally administered for 12 weeks<br>|
| Experimental: GSK1605786A, 500 milligrams twice daily<br>500 milligrams twice daily, orally administered for 12 weeks | Drug: GSK1605786A<br>* 500 milligrams twice daily, orally adminstered for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Response at Week 12 | Clinical response, defined as decrease in Crohn's disease activity index (CDAI) score, from Baseline value of >=100 points. Baseline defined as Week 0. CDAI is scoring system measuring disease severity with scores of >=220 to <=450 describing moderately-to-severely active population(higher score indicated severe disease). Contains 8 questions related to disease symptoms; soft tools in 7 days (weightage (Wt)as 2; abdominal pain over 7 days Wt= 5; general well being Wt= 7;Crohn's disease symptoms Wt=20; antidiarrhoeal medication used Wt=30; abdominal mass Wt=10; Anemia Wt=10; standard weight with Wt=1.Total CDAI score algorithmically derived from participants-reported above Crohn's disease symptoms and investigator recorded assessments, calculated by Interactive Voice Response System. Missing efficacy data, imputed using no effect imputation where missing was no response or no change in response (were non-responders). If baseline CDAI, < 100,participant was considered non-responder. | At Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Remission at Week 8, Week 12 and at Both Week 8 and Week 12 | Clinical remission is defined as a CDAI score of <150 points. CDAI is scoring system measuring disease severity with scores of >=220 to <=450 describing moderately-to-severely active population(higher score indicated severe disease). Contains 8 questions related to disease symptoms; soft tools in 7 days (weightage (Wt)as 2; abdominal pain over 7 days Wt= 5; general well being Wt= 7;Crohn's disease symptoms Wt=20; antidiarrhoeal medication used Wt=30; abdominal mass Wt=10; Anemia Wt=10; standard weight with Wt=1.Total CDAI score algorithmically derived from participants-reported above Crohn's disease symptoms and investigator recorded assessments, calculated by Interactive Voice Response System. Missing efficacy data, imputed using no effect imputation where missing was no response or no change in response (were non-responders). If the Baseline value was <150, the participant was not considered to have achieved remission. | Week 8 and Week 12 | 
| Percentage of Participants With a Clinical Response at Week 8 and at Both Week 8 and Week 12 | Clinical response, defined as decrease in Crohn's disease activity index (CDAI) score, from Baseline value of >=100 points. Baseline defined as Week 0. CDAI is scoring system measuring disease severity with scores of >=220 to <=450 describing moderately-to-severely active population(higher score indicated severe disease). Contains 8 questions related to disease symptoms; soft tools in 7 days (weightage (Wt)as 2; abdominal pain over 7 days Wt= 5; general well being Wt= 7;Crohn's disease symptoms Wt=20; antidiarrhoeal medication used Wt=30; abdominal mass Wt=10; Anemia Wt=10; standard weight with Wt=1.Total CDAI score algorithmically derived from participants-reported above Crohn's disease symptoms and investigator recorded assessments, calculated by Interactive Voice Response System. Missing efficacy data, imputed using no effect imputation where missing was no response or no change in response (were non-responders). If baseline CDAI, < 100,participant was considered non-responder. | Both Week 8 and Week 12 | 
| Change From Baseline in C-reactive Protein Concentration at Weeks 4, 8, and 12 | Blood samples were planned to be collected for the measurement of C-reactive protein at Baseline (Screening) and at Weeks 4, 8, and 12. Baseline is defined as the measurement at Screening (Day -21 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time points (Week 4, week 8 and week 12) minus the value at Baseline respectively. The study was terminated prematurely due to absence of favorable benefit-to-risk profile of GSK1605786A, and thus data for this outcome measure was not collected. | Baseline (Screening) and Weeks 4, 8, and Week 12 | 
| Change From Baseline in Faecal Calprotectin at Week 12 | Stool samples were planned to be collected for the measurement faecal calprotectin level at Baseline (Screening) and Week 12. Baseline is defined as the measurement at Screening (Day -21 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. The study was terminated prematurely due to absence of favorable benefit-to-risk profile of GSK1605786A, and thus data for this outcome measure was not collected. | Baseline (Screening) and Week 12 | 
| Pharmacokinetics (PK) of GSK1605786A | The PK analyses was planned to perform to characterize the PK of the study drug GSK1605786A, in the participant population. PK is defined as the concentration of drug in a participant's blood at certain time points after the drug was taken by mouth. PK sampling was to be conducted at week 2, 4, 6 ,8, 10 and week 12 (pre-dose, post-dose 0.5 hour (hr) to 2 hr, 3 to 6 hr, and 6 to 28 hr post-dose. The study was terminated prematurely due to absence of favorable benefit-to-risk profile of GSK1605786A, and thus the data for this outcome measure was not collected. | Baseline (Screening) and Week 12 | 
| Pharmacogenetic Analyses | Sample for the pharmacogenetic analyses was collected during any one of the Treatment Phase visit (Week 2, 4, 6, or 8 ). The pharmacogenetic analyses was planned to perform to investigate the relationship between the genetic markers with the safety and efficacy response to GSK1605786A. These pharmacogenetic analyses was not conducted following the early termination of the study. The study was terminated prematurely due to absence of favorable benefit-to-risk profile of GSK1605786A, and thus data was not collected for this outcome measure. | Post randomization any time during early two weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's disease, chemokine receptor 9 antagonist, Crohn's Disease Activity Index, active treatment