Clinical Trial: GSK2982772 Study in Ulcerative Colitis Patients

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Multicentre, Randomised, Double-blind (Sponsor Unblinded), Placebo-controlled Study With Open Label Extension to Investigate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, and Effi

Brief Summary:

This study is the first experience with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase inhibitor, in subjects with active ulcerative colitis (UC).

The primary objective will be to investigate the safety and tolerability of repeat oral doses of GSK2982772 60 mg or placebo twice daily for 42 days (Part A) followed by open label with GSK298772 60 mg twice daily for 42 days (Part B). In addition to pharmacokinetics (PK), a number of experimental and clinical endpoints will be employed to obtain information on the pharmacodynamics (PD), and preliminary efficacy in subjects with active UC. Although no formal hypothesis will be tested, these endpoints will enable a broader understanding of the mechanism of action and potential for clinical efficacy of GSK2982772 in UC.

Within 30 Days of screening visit, subjects will be randomized to receive either GSK2982772 60 mg or placebo orally twice daily for 42 Days (6 weeks) in a 2:1 ratio in Part A study. Subjects who complete the Part A study will move to open label Part B study to receive GSK2982772 60 mg twice daily for an additional 42 Days (6 weeks). After the open label (Part B) treatment period, subject will enter the Follow-up period which lasts for 28 Days (+/- 3 Days) post the last administration of study medication. The total duration of participation in the study will be approximately 20 Weeks from screening to the last study visit.


Detailed Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome:

  • Number of subjects with any adverse event (AE) and any serious adverse event (SAE) as a measure of safety and tolerability [ Time Frame: Up to follow-up (approximately Day 112) ]
    AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement.
  • Number of subjects with abnormal clinical chemistry parameters as a measure of safety and tolerability [ Time Frame: Up to follow-up (approximately Day 112) ]
    Blood samples will be collected to analyze blood urea nitrogen (BUN), creatinine, glucose (non-fasting), C Reactive Protein (CRP), low density lipoprotein cholesterol (LDL), potassium, sodium, calcium, triglycerides, aspartate amino-transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total cholesterol, total and direct bilirubin, total protein, albumin, high density lipoprotein cholesterol (HDL).
  • Number of subjects with abnormal hematology parameters as a measure of safety and tolerability [ Time Frame: Up to follow-up (approximately Day 112) ]
    Blood samples will be collected to analyze platelet count, red blood cells (RBC) levels, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), white blood cells (WBC) count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils).

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Number of subjects who achieve an absolute Mayo endoscopy subscore of 0 or 1 at Days 43 (Week 6) and 85 (Week 12) [ Time Frame: At Day 43 (Week 6) and Day 85 (Week 12) ]
      The Mayo Score is a 12-point scoring system used to assess UC disease activity based on stool frequency, rectal bleeding, endoscopic appearance and Physician's Global Assessment of Disease (PGA). A partial Mayo Score is a scoring system where disease activity is evaluated based on stool frequency, rectal bleeding and physician global assessment, without endoscopic components. Total and Partial Mayo Scores will be collected and scored centrally. The scores will be rated as normal if score is 0, mild if score is 1, moderate if score is 2 and severe if score is 3. Number of subjects who achieve an absolute Mayo endoscopy subscore of 0 or 1 at Days 43 (Week 6) and 85 (Week 12) will be reported.
    • Change from baseline in mucosal appearance determined by Ulcerative Colitis Endoscopic Index of Severity (UCEIS) [ Time Frame: Baseline (pre-dose on Day 1) and Day 85 (Week 12) ]
      UCEIS will be used as an additional tool to assess disease activity based on endoscopic vascular pattern, bleeding, erosions and ulcerations. It has been shown to accurately predict overall assessment of endoscopic severity of UC. The UCEIS is a scoring system UCEIS will be collected and scored centrally.
    • Change from baseline in the marker, mean CRP [ Time Frame: Baseline (pre-dose on Day 1) and up to approximately Day 112 ]
      A blood sample will be taken as part of the chemistry laboratory sample to measure CRP.
    • Change from baseline in the marker, fecal calprotectin (FCP) [ Time Frame: Baseline (pre-dose on Day 1) and up to approximately Day 85 ]
      A fecal sample will be taken to measure fecal calprotectin.
    • Change from baseline in histologic severity assessed by Modified Riley Score [ Time Frame: Baseline (pre-dose on Day 1) and up to approximately Day 85 ]
      The Modified Riley Score (MRS) is a 4 point scale (none, mild, moderate and severe) which scores histologic activity based on localization and quantification of neutrophils in the mucosa. Score is rated as none if score is 0, mild if score is in the range of 1 to 3, moderate if score is in the range of 4 to 6, severe if score is 7.
    • Change from baseline in histologic severity assessed by Geboes Index [ Time Frame: Baseline (pre-dose on Day 1) and up to approximately Day 85 ]
      Upon scoring of all components of the index, the highest grade with a subgrade above 0 will be recorded as a histological score.
    • Number of subjects who achieve clinical response at Days 43 (Week 6) and 85 (Week 12) [ Time Frame: At Day 43 (Week 6) and Day 85 (Week 12) ]
      Clinical response is defined as reduction by >=3 points or >=30 percent improvement from baseline complete Mayo score, along with a decrease in the rectal bleeding score of >=1 point, at Days 43 (Week 6) and 85 (Week 12).
    • Number of subjects who achieve clinical remission at Days 43 (Week 6) [ Time Frame: At Day 43 (Week 6) and Day 85 (Week 12) ]
      Clinical remission is defined as a complete Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, at Days 43 (Week 6) and 85 (Week 12).
    • Change from baseline in partial Mayo score [ Time Frame: Baseline (pre-dose on Day 1) and up to approximately Day 85 ]
      A partial Mayo Score is a scoring system where disease activity is evaluated based on stool frequency, rectal bleeding and physician global assessment, without endoscopic components. Partial Mayo Scores will be collected and scored centrally. The scores will be rated as normal if score is 0, mild if score is 1, moderate if score is 2 and severe if score is 3.
    • Measurement of pre-dose plasma concentrations of GSK2982772 [ Time Frame: Day 43 (Week 6) ]
      Pre-dose blood sample will be drawn on Day 43 for the measurement of plasma concentration of GSK2982772.
    • Measurement of post-dose plasma concentrations of GSK2982772 [ Time Frame: Day 1 and Day 43 (Week 6) ]
      Post-dose blood sample will be drawn on Days 1 and 43 at 1, 2, 4 and 6 hours for the measurement of plasma concentration of GSK2982772.
    • Measurement of trough concentrations of GSK2982772 [ Time Frame: Day 85 (Week 12) ]
      Post-dose blood sample will be drawn on Day 85 for the measurement of trough plasma concentration of GSK2982772.


    Original Secondary Outcome: Same as current

    Information By: GlaxoSmithKline

    Dates:
    Date Received: September 13, 2016
    Date Started: November 1, 2016
    Date Completion: November 28, 2018
    Last Updated: April 13, 2017
    Last Verified: April 2017