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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
255
500 milligrams once daily, orally administered for 12 weeks
500 milligrams twice daily, orally adminstered for 12 weeks
GSK Investigational Site
Little Rock, Arizona, United States
GSK Investigational Site
Tucson, Arizona, United States
GSK Investigational Site
La Jolla, California, United States
GSK Investigational Site
Aurora, Colorado, United States
GSK Investigational Site
Denver, Colorado, United States
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.
Time frame: At Week 12
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Post randomization any time during early two weeks
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GSK Investigational Site
Littleton, Colorado, United States
GSK Investigational Site
Hamden, Connecticut, United States
GSK Investigational Site
New Haven, Connecticut, United States
GSK Investigational Site
Washington D.C., District of Columbia, United States
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Jacksonville, Florida, United States
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