Primary:To investigate the safety and tolerability of 60 mg 3 times daily doses of GSK2982772 in subjects with moderate to severe ulcerative colitis.Secondary:To assess the preliminary efficacy, biomarkers, histological disease activity, response…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Adverse effects.
Secondary outcome
Mayo score, UCEIS, change from baseline of markers (incl. CRP and FCP),
Modified Riley Score and Geboes Index, plasma concentrations.
Background summary
This study is the first experience with GSK2982772, a receptor-interacting
protein-1 (RIP1) kinase inhibitor, in subjects with active ulcerative colitis
(UC) who are currently being treated with standard of care therapy. All
subjects will be allowed to continue standard of care therapy during the study,
provided that the medication type and dose is stable throughout the study.
RIP1 is a key signalling node which plays an essential role in inflammation and
cell death. Recent work has demonstrated that RIP1 catalytic kinase activity
can regulate TNF-mediated necroptosis and apoptosis. In addition, the
production of certain inflammatory cytokines can be regulated by RIP1 kinase
activity.
With the inhibition of RIP1 kinase activity with GSK2982772 may fill a unique
niche in the treatment of inflammatory conditions through multiple mechanisms,
including inhibition of inflammation-induced cell death (necroptosis and
apoptosis) and inhibition of the production of certain pro-inflammatory
cytokines.
Study objective
Primary:
To investigate the safety and tolerability of 60 mg 3 times daily doses of
GSK2982772 in subjects with moderate to severe ulcerative colitis.
Secondary:
To assess the preliminary efficacy, biomarkers, histological disease activity,
response and remission, pharmacokinetics.
Study design
Double blind multicenter placebo controlled parallel group study. Randomization
(1:1) to 3 times daily
• GSK2982772 60 mg
• Placebo.
Screening 30 days, treatment phase part A (double blind) 42 days, treatment
phase part B (open label GSK2982772 only) 42 days, follow-up 28 days.
Approx. 36 subjects. Should the dropout rate in Part A be higher than
anticipated, or the sample size review warrants an increase in randomized
subjects, additional subjects may be randomized (up to a maximum of 48).
Intervention
Treatment with GSK2982772 (treatment phase part A and B) or placebo (part A
only) on top of standard therapy.
Study burden and risks
Risk: Adverse events of the study medication and the sigmoidoscopy.
Burden:
9 visits and 6 telephone calls in 20 weeks. At the end of the double blind
period, one day may not be enough to perform all tests. An extra day may be
added.
Physical examination: 9 times.
Blood draws: 9 times (200-225 ml blood in total).
Faecal examination: 8 times.
Pregnancy test: 9 times.
ECG: 9 times.
Sigmoidoscopy plus biopsy: 3 times.
Diary entire study period: Medication intake and adverse events.
Questionnaires (Columbia Suicide Severity Rating Scale, IBDQ) 4 times.
Optional: blood sample for pharmacogenetics.
Huis ter Heideweg 62
Zeist 3705 LZ
NL
Huis ter Heideweg 62
Zeist 3705 LZ
NL
Listed location countries
Age
Inclusion criteria
• Between 18 and 75 years of age inclusive.
• Confirmed diagnosis of active UC, as documented by complete diagnostic colonoscopy to the terminal ileum with biopsy at least 3 months prior to screening.
• Complete Mayo Score of >=3 points and endoscopy sub score of 2 to 3 at screening, despite concurrent treatment with at least oral corticosteroids or 5-ASA or purine analogues or all. See protocol page 28 for details.
• Naive to any biological therapies for UC or previous exposure to a single anti-TNF biologic agent which was discontinued for reasons other than primary non-response more than 8 weeks (or 5 half lives whichever is longer) prior to first dose or previous exposure to a single anti-TNF biologic agent in the context of a clinical trial which was discontinued more than 8 weeks (or 5 half lives whichever is longer) prior to first dose.
• BMI 18.5 - 35 kg/m2 (inclusive).
• Females must not be pregnant of lactating.
• Females of childbearing potential and males must comply with the contraception requirements outlined on page 29 of the protocol.
Exclusion criteria
• Indeterminate colitis, Crohn*s Disease, infectious colitis, or ischemic colitis.
• Fulminant UC, or UC limited to the rectum (disease extent <15 cm from the anal verge).
• Previous small bowel or colonic surgery, histological evidence of colonic dysplasia or bowel stricture.
• Colostomy, fistulae or known symptomatic stenosis of the intestine.
• Clostridium difficile toxin test or active/previous colonic CMV infection.
• Suicidal ideation behaviour as measures using the Columbia Suicide Severity Rating Scale or history of attempted suicide.
• Active infection, or a history of infections. See protocol page 30-31 for details.
• Treatment with the therapies listed in Section 6.11.2, or changes to those treatments, within the prescribed timeframe.
• Received a live or attenuated vaccine within 30 days of randomization or plan to receive a vaccination during the study until 5 half-lives (or 2 days) plus 30 days after receiving GSK2982772.
• Presence of HBsAg, positive hepatitis C antibody test result. Positive serology for HIV.
• Exposure to more than 4 investigational medicinal products within 12 months prior to the first dose.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-001833-29-NL |
| CCMO | NL58479.018.17 |
| Other | www.gskclinicalstudyregister.com, nummer 202152 |