GSK1605786A in the Maintenance of Remission in Subjects With Crohn's Disease

Study Overview
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Brief Summary
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A randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of two doses (500 mg once daily and 500 mg twice daily) of GSK1605786A in maintaining remission over 52 weeks in adult subjects with Crohn's disease. Efficacy will be assessed by the Crohn's Disease Activity Index (CDAI) score. Eligible subjects will have achieved response (CDAI decrease of at least 100 points) and/or remission (CDAI less than 150) in a prior GSK sponsored induction study. The primary endpoint will be proportion of subjects in remission at both Weeks 28 and 52. Safety will be assessed by recording of adverse events, clinical laboratory parameters including liver function tests, vital signs and electrocardiogram. Population pharmacokinetics will evaluate the two doses of GSK1605786A. Health outcomes assessments will include changes in Inflammatory Bowel Disease Questionnaire (IBDQ), SF-36v2, EQ-5D, Work Productivity and Activity Impairment - Crohn's Disease (WPAI-CD) and disability.

Detailed Description
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This is a multi-centre, randomised, placebo-controlled, double-blind parallel group study in adult subjects with Crohn's disease who previously achieved clinical response (CDAI decrease of at least 100 points) and/or remission (CDAI less than 150) in a prior Phase III induction study (Study CCX114151 or another GSK sponsored induction study). Subjects will be randomised to 52 weeks of oral treatment with GSK1605786A 500 mg once daily or 500 mg twice daily or placebo. Subjects who are receiving concomitant corticosteroids at entry will undergo dose tapering following a defined schedule. Subjects who complete the treatment period may be eligible to enter an open-label extension study. Subjects who experience disease worsening and require additional (rescue) treatment will be withdrawn and may be eligible to enter the open-label study. Subjects who do not enter the open-label study must complete a follow-up assessment 4 weeks after completion of treatment. Approximately 756 subjects will be enrolled.

Official Title
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A 52 Week Randomised, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of GSK1605786A in the Maintenance of Remission in Subjects With Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: GSK1605786A
* Drug: Placebo
* Drug: GSK1605786A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects achieving clinical response (CDAI decrease of at least 100 points) and/or remission (CDAI less than 150) upon completion of treatment in Study CCX114151 or another GSK sponsored induction study Written informed consent prior to any CCX114157 specific study procedures Females of child-bearing potential must be sexually inactive or commit to use of consistent and correct use of contraceptive methods with a failure rate of less than 1 percent Stable doses of Crohn's disease medications Subjects on corticosteroids at entry must be willing to undergo corticosteroid dose taper during the study Exclusion Criteria: If female, is pregnant, has a positive pregnancy test or is breast-feeding Subjects with known or suspected coeliac disease or a positive screening test (anti-tissue transglutaminase antibodies) should have been excluded from enrolment into the induction studies. Subjects in whom a diagnosis of coeliac disease is subsequently suspected should have this excluded with testing for anti-tissue transglutaminase antibodies prior to enrolment into the maintenance study. Known or suspected fixed symptomatic small bowel stricture Enterocutaneous, abdominal or pelvic fistulae likely to require surgery during the study period Current sepsis or infections requiring intravenous antibiotic therapy for greater than 2 weeks Evidence of hepatic dysfunction, viral hepatitis, or liver function abnormalities

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|
| Experimental: GSK1605786A once daily<br>500 milligrams once daily | Drug: GSK1605786A<br>* GSK1605786A 500 milligrams once daily<br>|
| Experimental: GSK1605786A twice daily<br>500 milligrams twice daily | Drug: GSK1605786A<br>* GSK1605786A 500 milligrams twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Clinical Remission (Crohn's Disease Activity Index , CDAI Score <150 Points) at Both Weeks 28 and 52 of the 52-week Treatment Period | Clinical remission is defined as a CDAI score <150 points. In the missing=no effect imputation, participants with missing CDAI scores was considered not to be in clinical remission. Data for percentage of participants in at both Weeks 28 and 52 of the 52-week treatment period have been presented. | Week 28 and 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Clinical Remission (CDAI Score <150 Points) and Not Taking Corticosteroids at Both Weeks 28 and 52 of the 52-week Treatment Period | Clinical remission is defined as a CDAI score <150 points. A participant was considered to be not taking corticosteroids at Weeks 28 and 52 if the participant had not taken a corticosteroid for the 8 days prior to and the day of the CDAI assessment for each of Weeks 28 and 52. In the missing=no effect imputation, participants with missing CDAI scores was considered not to be in clinical remission. Data for percentage of participants in clinical remission and not taking corticosteroids at both Weeks 28 and 52 of the 52-week treatment period have been presented. | Week 28 and 52 | 
| Percentage of Participants in Clinical Remission at Both Weeks 28 and 52 of the 52-week Treatment Period Among Those Participants Who Were in Clinical Remission at Baseline | Clinical remission is defined as a CDAI score <150 points. Among participants in remission at baseline, the percentage of participants with clinical remission at both Weeks 28 and 52 of the treatment period using the no effect imputation for missing data were to be compared between each GSK1605786A dose group and placebo using Fisher's exact test. Participants with missing CDAI scores were to be considered not to be in remission according to the missing=no effect imputation. The limited data resulting from early termination of Study CCX114157 did not allow any conclusions to be drawn about the efficacy of GSK1605786A in the maintenance of clinical remission in participants with Crohn's disease. | Week 28 and 52 | 
| Percentage of Participants in Clinical Remission at All Visits (Continuous Clinical Remission) During the 52-week Treatment Period Among Participants in Clinical Remission at Baseline | The percentage of participants with clinical remission at all visits during the 52-week treatment period were to be summarized by treatment group for the subset of participants in remission at baseline, using the no effect imputation for missing data. Participants with missing CDAI scores were to be considered not to be in remission according to the missing=no effect imputation. Comparisons between each GSK1605786A dose group and placebo were to be made using Fisher's exact test.The limited data resulting from early termination of Study CCX114157 did not allow any conclusions to be drawn about the efficacy of GSK1605786A in the maintenance of clinical remission in participants with Crohn's disease. | Upto Week 52 | 
| Percentage of Participants in Clinical Remission at Week 52 | The limited data resulting from early termination of Study CCX114157 did not allow any conclusions to be drawn about the efficacy of GSK1605786A in the maintenance of clinical remission in participants with Crohn's disease. | Week 52 | 
| Percentage of Participants With a Clinical Response (CDAI Decrease >=100 Points) at Both Weeks 28 and 52 of the 52-week Treatment Period | Clinical response is defined as a reduction from the induction study baseline CDAI score of >=100 points. The percentage of participants with a clinical response at both Weeks 28 and 52 of the 52-week maintenance treatment period in the ITT population using the no effect imputation for missing data were to be compared between each GSK1605786A dose group and placebo using Fisher's exact test. Participants with missing CDAI scores were to be considered non-responders according to the missing=no effect imputation. The limited data resulting from early termination of Study CCX114157 did not allow any conclusions to be drawn about the efficacy of GSK1605786A in the maintenance of clinical remission in participants with Crohn's disease. | Week 28 and 52 | 
| Time to Induction of Clinical Remission in Participants Who Had Achieved Clinical Response During Induction Therapy But Were Not in Clinical Remission at Baseline | The duration of time participants maintained clinical remission during the 52-week treatment period was to be defined as the time between Week 0 and the first visit where remission was not observed in those participants in remission at baseline. These time periods were to be summarized by treatment group using quartiles and their corresponding confidence intervals. Comparisons between each GSK1605786A dose group and placebo were to be made using log-rank tests. The limited data resulting from early termination of Study CCX114157 did not allow any conclusions to be drawn about the efficacy of GSK1605786A in the maintenance of clinical remission in participants with Crohn's disease. | Upto Week 52 | 
| Change From Baseline in CDAI Score at Weeks 4, 8, 12, 20, 28, 36, 44, and 52 | The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A score of 150 or below indicates remission and a score above 450 indicates extremely severe disease. A decrease in CDAI over time indicates improvement in disease activity. CDAI scores and changes in CDAI scores during the 52-week treatment period were to be summarized by treatment group at Weeks 4, 8, 12, 20, 28, 36, 44, and 52. The limited data resulting from early termination of Study CCX114157 did not allow any conclusions to be drawn about the efficacy of GSK1605786A in the maintenance of clinical remission in participants with Crohn's disease. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 4, 8, 12, 20, 28, 36, 44, and 52 | 
| Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52 | The IBDQ consists of a self-administered 32-item questionnaire that evaluates quality of life across 4 dimensional scores: Bowel, Systemic, Social and Emotional. The IBDQ questionnaire was to be completed by each participant at baseline and at Weeks 28, and 52. The response to each question can range from 1 to 7, with 1 indicating severe problem and 7 indicating normal health. The total IBDQ is computed as the sum of the responses to the individual IBDQ questions. The total score can range between 32 to 224 with higher scores indicating a better quality of life. The limited data resulting from early termination of Study CCX114157 did not allow any conclusions to be drawn about the efficacy of GSK1605786A in the maintenance of clinical remission in participants with Crohn's disease. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Week 52 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury. | Upto 56 weeks | 
| Change From Baseline in Vital Sign Systolic Blood Pressure Systolic (SBP) and Diastolic Blood Pressure (DBP) Upto Week 56 | Vital sign assessments included SBP and DBP collected in supine position following 5 minutes of rest. Assessments were carried out at Weeks 4, 8, 12, 20, 28, 36, 44, 52 and Week 56. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 4, 8, 12, 20, 28, 36, 44, 52, 56 | 
| Change From Baseline in Vital Sign Heart Rate Upto Week 56 | Vital sign assessment included heart rate collected in supine position following 5 minutes of rest. Assessments were carried out at Weeks 4, 8, 12, 20, 28, 36, 44, 52 and 56. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 4, 8, 12, 20, 28, 36, 44, 52 and 56 | 
| Number of Participants With Shift From Baseline in Hematology Parameters | Hematology parameters included platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils, hematocrit, red blood cell count, hemoglobin, white blood cell count and segmented neutrophils . Assessments were carried out at Weeks 4, 8, 12, 20, 28, 36, 44 and 52 and 56. The consolidated data for number of participants with shift from Baseline (change from Baseline) in hematology parameters characterized as high and low have been presented. | Upto Week 56 | 
| Number of Participants With Shift From Baseline in Clinical Chemistry Parameters | Clinical chemistry parameters included total protein, phosphorous, albumin, sodium, potassium, chloride, calcium, glucose, gamma glutamyl transferase, total bilirubin, direct bilirubin, alkaline phosphatase, alanine amino transferase, aspartate amino transferase, blood urea nitrogen (BUN)/Urea, creatinine, uric acid, lactate dehydrogenase, bicarbonate, cholesterol and creatinine kinase. Assessments were carried out at Weeks 4, 8, 12, 20, 28, 36, 44, 52 and 56. The consolidated data for number of participants with shift from Baseline (change from Baseline) in clinical chemistry parameters characterized as high and low have been presented. | Upto Week 56 | 
| Change From Baseline in Liver Function Test Parameter Total Bilirubin at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 and 56. | Liver function test parameter included total bilirubin. Assessments were carried out at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 and 56. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 and 56. | 
| Change From Baseline in Liver Function Test Parameter Albumin at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56 | Liver function test parameter included albumin. Assessments were carried out at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56.Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56 | 
| Change From Baseline in Liver Function Test Parameter Alanine Amino Transferase, Aspartate Amino Transferase, Alkaline Phosphatase and Gamma Glutamyl Transferase at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56 | Liver function test parameters included alanine amino transferase, aspartate amino transferase, alkaline phosphatase and gamma glutamyl transferase. Assessments were carried out at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56 | 
| Number of Participants With 12 Lead Electocardiogram (ECG) Abnormalities at Week 28 and 52 | A 12 lead ECG was collected at Weeks 28 and 52. ECG abnormalities were characterized as abnormal-not clinically significant (A-NCS) and abnormal-clinically significant (A-CS). A-NCS data for Week 28 and 52 have been presented. | Week 28 and 52 | 
| Change From Baseline in Short Form - 36 Version 2 (SF-36 v2) at Weeks 28 and 52 | The SF-36v2 health survey is a self-administered, generic, 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning, role-physical, bodily pain, general health perceptions, vitality, social functioning, role-emotional, and mental health. Each domain is scored from 0 (poorer health) to 100 (better health). SF-36 v2 items are scored such that a higher score indicates a better health state and better functioning. Data for change from Baseline in SF-36 v2 at Weeks 28 and 52 was not collected following early termination of this study. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 28 and 52 | 
| Change From Baseline in European Quality of Life (EuroQol ) Five Dimensions Questionnaire (EQ-5D) at Weeks 28 and 52 | EQ-5D self-reported questionnaire is used to measure health-related quality of life by measuring 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D questionnaire includes a visual analog scale (VAS) which records participants self-rated health status on a graduated (0-100) scale with higher scores indicating higher Health-Related Quality of Life (HRQoL). Data for Change from Baseline in EuroQol five dimensions questionnaire (EQ-5D) at Weeks 28 and 52 was not collected following early termination of this study. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 28 and 52 | 
| Change From Baseline in Work Productivity & Activity Impairment - Crohn's Disease (WPAI-CD) at Weeks 28 and 52 | WPAI measures the effect of your CD on your ability to work and perform regular activities. 6-items assess impairment in work productivity and daily activity during the 7 days before the assessment. It measures the percentage of overall impairment in work productivity and daily activity due to CD. A WPAI score of 0% = no impairment and a score of 100% = total loss of work productivity or activity. An absolute change in WPAI score of 7% is considered the minimum clinically important difference (MCID). Data for change from Baseline in WPAI-CD at Weeks 28 and 52 was not collected following early termination of this study. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 28 and 52 | 
| Receipt of Disability Benefits at Weeks 28 and 52 | Receipt of disability benefits (Yes/No) was to be recorded at Weeks 0, 28 and 52 and Early Withdrawal visit if applicable. Change from baseline in receipt of disability benefits was to be compared between participants in remission versus participants not in remission using a Wilcoxon rank sum test. Data for Receipt of disability benefits at Weeks 28 and 52 was not collected following early termination of this study. | Weeks 28 and 52 | 
| Change From Baseline in Health-related Resource Utilization at Weeks 28 and 52 | Healthcare related resource utilization was to include: Hospitalizations (all cause and Crohn's disease related), Length of stay, Surgical procedures (all cause and Crohn's disease related), Outpatient visits (all cause and Crohn's disease related ). The frequency of hospitalizations, surgical procedures and hospital out-patient visits were to be recorded at Weeks 28 and 52. The number and percentage of participants reporting all cause and Crohn's disease -related hospitalizations, surgeries, and hospital out-patient visits were to be summarized and compared between each GSK1605786A dose group and placebo using Fisher's exact test. Data for Change from Baseline in health-related resource utilization at Weeks 28 and 52 was not collected following early termination of this study. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 28 and 52 | 
| Change From Baseline in C Reactive Protein (CRP) at Weeks 28 and 52 | C-reactive protein (CRP) at was to be assessed at Weeks 4, 8, 12, 20, 28, 36, 44, 52 visit if applicable. Data for Change from Baseline in C reactive protein (CRP) at Weeks 28 and 52 was not collected following early termination of this study. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0 and Weeks 28 and 52 | 
| Change From Baseline in Faecal Calprotectin at Weeks 28 and 52 | Stool sample for faecal calprotectin were to be collected at Weeks 28 and 52 visit if applicable. Data for Change from baseline in faecal calprotectin at Weeks 28 and 52 was not collected following early termination of this study. Baseline was defined as value at Week 0. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment. | Baseline (Week 0) and Weeks 28 and 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's disease, oral CCR9 antagonist, placebo-controlled, maintenance of remission, 52-week treatment, quality of life