A Study To Investigate The Safety And Possible Clinical Benefit Of Multistem(r) In Patients With Moderate To Severe Ulcerative Colitis

• Incidence and severity of adverse events (at Weeks 4, 8, 12 and 16). [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
• Change from baseline of endoscopic score at Week 8 as measured by modified Baron score. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Change from baseline of Mayo rectal bleeding sub-score at Week 4. [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Change from baseline of Mayo rectal bleeding sub-score at Week 8. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

• Incidence and severity of adverse events (at Week 4 as well as at Week 8). [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
• Change from baseline of endoscopic score at Week 8 as measured by modified Baron score. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Change from baseline of Mayo rectal bleeding sub-score at Week 8. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

• Changes in laboratory measurements of safety and vital signs (at Weeks 4, 8, 12 and 16). [ Time Frame: 16weeks ] [ Designated as safety issue: Yes ]
• Change from baseline of Mayo rectal bleeding sub-score at Weeks 12 and 16. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Changes from baseline at Weeks 4, 8, 12 and 16, in the following biomarker levels: fecal calprotectin, CRP. [ Time Frame: 16weeks ] [ Designated as safety issue: No ]
• Proportions of subjects with a Mayo rectal bleeding sub-score equal 0 at Weeks 4, 8, 12 and 16. [ Time Frame: 8,16weeks ] [ Designated as safety issue: No ]
• Proportion of subjects in endoscopic remission at Week 8 (defined as subjects with a modified Baron endoscopic score equal 0). [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportion of subjects in clinical remission at Week 8 (defined as a total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point). [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportions of subjects with a decrease from baseline of at least one point in Mayo rectal bleeding sub-score at Weeks 4, 8, 12 and 16. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Proportion of subjects with an endoscopic response at Week 8 (defined as a decrease in modified Baron endoscopic score from baseline of at least 2 points). [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportion of subjects with a clinical response at Week 8 (defined as a decrease in total Mayo score from baseline in Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the sub-score for rectal bleeding of at least [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• 1 point or an absolute sub-score for rectal bleeding of 0 or 1). [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Change from baseline in total Mayo score at Week 8. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Changes from baseline in partial Mayo score at Weeks 4, 8, 12 and 16. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Patient-reported rectal bleeding scores, to be modeled longitudinally up to and including Week 16. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Changes in biopsy histology score at Week 8 (measured by Riley Index). [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

• Changes in laboratory measurements of safety and vital signs (at Week 4 as well as at Week 8). [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
• Changes from baseline at Week 4 as well as at Week 8 in the following biomarker levels: fecal calprotectin, CRP. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportion of subjects with a Mayo rectal bleeding sub-score equal 0 at Week 4 as well as at Week 8. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportion of subjects in endoscopic remission at Week 8 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportions of subjects in clinical remission at Week 8 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportions of subjects with a decrease from baseline of at least one point in Mayo rectal bleeding sub-score at Week 4 as well as at Week 8. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportion of subjects with an endoscopic response at Week 8 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportion of subjects with clinical response at Week 8 [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Changes from baseline in total Mayo score at Week 8. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Changes from baseline in partial Mayo score at Week 2, Week 4, Week 6, as well as at Week 8. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Daily patient-reported rectal bleeding scores, to be modeled longitudinally. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Change from baseline of Mayo rectal bleeding sub-score at Week 4. [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Changes in biopsy histology score at Week 8 (measured by Riley Index). [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

MultiStem(r) is a new biological product, manufactured from human stem cells obtained from adult bone marrow or other nonembryonic tissue sources. Factors expressed by MultiStem cells are believed to reduce inflammation and regulate immune system function, protect damaged or injured cells and tissue, promote formation of new blood vessels, and augment tissue repair and healing. MultiStem cell treatment resulted in significant efficacy in a mouse model of Graft versus Host Disease with almost complete reversal of gastrointestinal pathology (similar to pathology that would be expected in Ulcerative Colitis). These data, together with safety data generated in 2 other clinical trials, suggest that MultiStem has the potential to be a new treatment option for patients with ulcerative colitis. This is the first study of MultiStem in this patient population and will cautiously explore the safety/toleration and potential benefit of this new treatment in patients with moderate to severe disease.

• Drug: placebo
  once every 7 days for 1- 3 doses
• Drug: MultiStem low dose
  1-3 doses.
• Drug: placebo
  Single dose at week 8
• Drug: MultiStem low dose
  Single dose at week 8
• Drug: placebo
  Single dose Day 1
• Drug: MultiStem high dose
  Single dose Day 1
• Drug: MultiStem high dose
  Single dose at week 8

• Experimental: Cohort 1
  The first 9 subjects will be recruited into Cohort 1 and will receive either placebo (n=3) or MultiStem low dose (n=6) as an intravenous infusion on Day 1. The first five patients enrolled constitute a subgroup of Cohort 1 and these patients will receive multiple doses, once every day for 7 days for 3 doses (Day 1 and Weeks 1 & 2).
  Interventions:

  • Drug: placebo
  • Drug: MultiStem low dose
  • Drug: placebo
  • Drug: MultiStem low dose
• Experimental: Cohort 2
  This group will receive either placebo (n=3) or MultiStem high dose (n=6) as an intravenous infusion on Day 1. The subjects then receive the opposite dose of study medication at Week 8.
  Interventions:

  • Drug: placebo
  • Drug: MultiStem high dose
  • Drug: placebo
  • Drug: MultiStem high dose
• Experimental: Cohort 3
  These subjects will receive either Placebo or MultiStem (1:1 randomization) as an intravenous infusion on Day 1. In addition all subjects in Cohort 3 will receive a single infusion of either MultiStem or Placebo at Week 8, depending on their randomization schedule. A total of ~22 patients will receive an additional infusion of MultiStem, ~44 patients will receive the alternative blinded therapy to that which they received for Day 1 infusion, and ~22 patients will receive an additional infusion of placebo.
  Interventions:

  • Drug: placebo
  • Drug: MultiStem high dose
  • Drug: placebo
  • Drug: MultiStem high dose

Inclusion Criteria:

• Subjects must have a documented diagnosis of ulcerative colitis at least 6 months prior to screening.
• Subjects must have active moderate-to-severe ulcerative colitis based on Mayo score.
• Subjects must have Modified Baron endoscopic score of at least 2 determined within 7 days of first dosing.
• Subjects must have failed or be intolerant (as determined by the investigator) of at least one of the following treatments for UC: Oral corticosteroids, azathioprine or 6-mercaptopurine (6-MP), or anti-tumor necrosis factor (TNF) therapy, eg, infliximab or adalimumab.

Exclusion Criteria:

• Subjects who have abnormal organ and marrow function.
• Subjects with a diagnosis of indeterminate colitis, or clinical findings suggestive of Crohn's disease.
• Subjects who meet Truelove-Witts criteria for severe ulcerative colitis.
• Subjects receiving or who are expected to receive Infliximab or other biologic treatment within 8 weeks of the Day 1 study visit.
• Subjects receiving or who are expected to receive Cyclosporine, mycophenolate, or tacrolimus within 4 weeks of the Day 1 study visit.