A Multicentre, Randomised, Double-blind, Placebo-controlled, Repeat Dose, Dose-ranging Phase 2a/2b Study to Evaluate the Safety, Tolerability and Efficacy of an Anti-oncostatin M Monoclonal Antibody (GSK2330811) in Patients With Moderate to Severe Crohn's Disease
Overview
- Phase
- Phase 2
- Intervention
- Placebo
- Conditions
- Crohns Disease
- Sponsor
- GlaxoSmithKline
- Primary Endpoint
- Percentage of participants with endoscopic response measured by Simple Endoscopic score for Crohn's Disease (SES-CD) at Week 12
- Status
- Withdrawn
- Last Updated
- 4 years ago
Overview
Brief Summary
The study will include participants with moderate to severe Crohn's disease. The aim is to evaluate the safety, tolerability, and efficacy of anti-oncostatin M monoclonal antibody (mAb) GSK2330811. This is a parallel group study with Induction and Maintenance periods. During Induction, the first 100 participants randomised will receive a 450mg GSK2330811 SC loading dose followed by 150mg weekly (Q1W), or placebo for 12 weeks. Additional dose-ranging arms will open after the 100th participant is randomized and in addition to placebo and the highest dose arms will also include a 300mg subcutaneous (SC) loading dose followed by 150mg SC every 2 weeks (Q2W) arm, a 300mg loading dose followed by 150mg SC every 4 weeks (Q4W) arm and a 150mg SC every 8 weeks (Q8W) arm. Participants with a clinical response at Week 12 will continue into a 40-week blinded maintenance period and will receive either 150mg SC Q2W, 150mg SC Q4W, 150mg SC Q8W or placebo. Participants without a clinical response at Week 12 will be offered up to 40 weeks of open label treatment with GSK2330811. Approximately 560 participants will be screened to randomize 280.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participant must be 18 years of age or over at the time of signing the informed consent.
- •Participants who have a diagnosis of Crohn's Disease, established at least 3 months prior to first screening visit, supported by radiologic, histologic and/or endoscopic findings, and are expected to be able to be managed on an outpatient basis, if clinical course does not worsen.
- •Participants who have active colitis and/or ileitis at screening, confirmed by centrally-read ileo-colonoscopy, defined as a baseline SES-CD score of \>= 7 (\>= 4 if disease confined to the terminal ileum) and \<=
- •Participants who have active clinical disease at Baseline, measured by PRO2, defined as a 7-day average SF \>= 4 and/or a 7-day average AP \>=
- •Participants who have a history of at least one of the following: Inadequate response to, loss of response to, or intolerance to conventional immunosuppression (i.e. azathioprine, 6-mercaptopurine, methotrexate); Inadequate response to, loss of response to, intolerance to, or demonstrated dependence on oral corticosteroids; Inadequate response to, loss of response to, or intolerance to biologic therapy or small molecule JAK inhibitors.
- •Participants with Baseline body mass index (BMI) \>= 18.5 kilogram per square meter (kg/m\^2).
- •Male and Female participants are both eligible to participate.
- •A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or A WOCBP who agrees to use a contraceptive method that is highly effective, with a failure rate of \<1 percent, from 28 days prior to first dosing day (Day 1), during the dosing period and for at least 126 days (18 weeks) after the last dose of study treatment, corresponding to the time needed to eliminate any study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
- •Participant who is capable of giving signed informed consent.
Exclusion Criteria
- •Participants with a current diagnosis of indeterminate colitis, inflammatory bowel disease (unclassified), infectious colitis, lymphocytic colitis, microscopic colitis, radiation colitis, ischemic colitis or ulcerative colitis.
- •Participants with complications of Crohn's disease including strictures, adhesions, stenosis, short bowel syndrome and any other manifestation, if it is anticipated to require surgery during the study or that could interfere with study assessments (including but not limited to symptomatic strictures or stenosis) or that may confound the evaluation of benefit from treatment with GSK
- •A current ileostomy or colostomy.
- •Any bowel resection or diversion within 6 months or other intra-abdominal surgery within 3 months prior to the screening ileo-colonoscopy.
- •Receiving tube feeding, defined formula diets, or total parenteral nutrition within 4 weeks prior to the screening ileo-colonoscopy.
- •Current or prior abscess (proven or suspected) unless drained and adequately treated at least 3 weeks prior to the screening ileo-colonoscopy for cutaneous and perianal abscesses and at least 8 weeks prior to the screening ileo-colonoscopy for intra-abdominal abscesses. There must be no anticipated need for further surgery during the study.
- •Active fistulas associated with an abscess and anticipated need for surgery during the study. If a fistula is present, it should have established drainage.
- •Prior fecal micro-biota transplant within 3 months prior to the screening ileo-colonoscopy.
- •Participants with any uncontrolled medical conditions, other than active Crohn's Disease, that in the opinion of the investigator puts the participant at unacceptable risk or likely will interfere with study assessments or data integrity. Other medical conditions should be stable at the time of screening expected to remain stable for the duration of the study.
- •Known history of or current bleeding or coagulation disorder.
Arms & Interventions
Participants receiving placebo
Participants will receive placebo loading dose followed by placebo for 12 weeks during Induction phase. Participants with clinical response at Week 12 will continue to receive placebo into a 40-weeks blinded maintenance period. Participants without a clinical response at Week 12 will receive a 450mg GSK2330811 SC loading dose at Week 12, followed by 150 mg SC every week from Week 13 until Week 23, followed by 150 mg SC every 2 weeks until Week 50.
Intervention: Placebo
Participants receiving GSK2330811 450mg loading dose/150mg Q1W
Participants will receive 450mg GSK2330811 SC as loading dose followed by 150 mg GSK2330811 Q1W for 12 weeks during Induction period. Participants with clinical response at Week 12 will continue into a 40 weeks blinded maintenance period will receive 150 mg GSK2330811 SC Q2W. Participants without a clinical response will receive GSK2330811 150mg Q1W from Week 12 until Week 23, followed by GSK2330811 150mg Q2W until Week 50.
Intervention: GSK2330811
Participants receiving GSK2330811 300mg loading dose/150mg Q2W
Participants will receive 300mg GSK2330811 SC as loading dose followed by 150mg GSK2330811 SC Q2W for 12 weeks during Induction period. Participants with clinical response at Week 12 will continue into a 40 weeks blinded maintenance period will receive 150mg GSK2330811 SC Q2W. Participants without a clinical response will receive GSK2330811 150mg Q1W from Week 12 until Week 23, followed by GSK2330811 150mg Q2W until Week 50.
Intervention: GSK2330811
Participants receiving GSK2330811 300mg loading dose/150mg Q4W
Participants will receive 300mg GSK2330811 SC as loading dose followed by 150mg GSK2330811 SC Q4W for 12 weeks during Induction period. Participants with clinical response at Week 12 will continue into a 40 weeks blinded maintenance period will receive 150 mg GSK2330811 SC Q4W. Participants without a clinical response will receive GSK2330811 150mg Q1W from Week 12 until Week 23, followed by GSK2330811 150mg Q2W until Week 50.
Intervention: GSK2330811
Participants receiving GSK2330811 150mg Q8W
Participants will receive GSK2330811 SC 150 mg Q8W for 12 weeks during Induction period. Participants with clinical response at Week 12 will continue into a 40 weeks blinded maintenance period will receive 150 mg GSK2330811 SC Q8W. Participants without a clinical response will receive GSK2330811 150mg Q1W from Week 12 until Week 23, followed by GSK2330811 150mg Q2W until Week 50.
Intervention: GSK2330811
Outcomes
Primary Outcomes
Percentage of participants with endoscopic response measured by Simple Endoscopic score for Crohn's Disease (SES-CD) at Week 12
Time Frame: Week 12
The SES-CD is a validated tool for grading the endoscopic severity of active Crohn's disease based on an assessment of the size of individual ulcers, the proportion of the surface that is abnormal and the proportion of the surface that is ulcerated, and the presence or absence of visible stenosis. The attributes are scored across 5 bowel segments and combined to give an SES-CD score ranging from 0 to 56 (higher scores represent more severe endoscopic disease involvement). SES-CD will be determined for each endoscopy using a central reading algorithm. Endoscopic response is defined as \>= 50 percent decrease from Baseline in SES-CD
Secondary Outcomes
- Percentage of participants with endoscopic response based on dose response relationship at Week 12 measured by SES-CD(Week 12)
- Percentage of participants with absence of mucosal ulceration on endoscopy at Week 12(Week 12)
- Area Under the Concentration Time Curve Over the Dosing Period (AUC [0-tau]) of GSK2330811(Pre-dose on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 10, and 12)
- Number of participants with anti-drug antibodies(Pre-dose on Day 1 and Weeks 4, 8 and 12)
- Change from Baseline in SES-CD at Week 12(Baseline (within 35 days prior to Day 1) and Week 12)
- Percentage of participants in endoscopic remission at Week 12(Week 12)
- Percentage of participants in clinical remission at Week 12 measured by PRO2(Week 12)
- Change from Baseline in serum C-reactive protein at Week 12(Baseline (Day 1) and Week 12)
- Trough Concentration at steady state (Ctrough ss)(Pre-dose on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 10, and 12)
- Percentage of participants with clinical response measured by Patient Reported Outcome 2 (PRO2) at Week 12(Week 12)
- Plasma concentration of GSK2330811(Pre-dose on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 10, and 12)
- Change from Baseline in fecal calprotectin at Week 12(Baseline (Day 1) and Week 12)
- Serum levels of free Oncostatin M (OSM)(Pre-dose on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 10, and 12)
- Serum levels of total OSM(Pre-dose on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 10, and 12)