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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2 Randomized, Double-blind, Placebo-controlled, Parallel Group, Multi-center Study To Investigate The Safety And Efficacy Of Multistem (Pf-05285401) In Subjects With Moderate To Severe Ulcerative Colitis

Conditions
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Colitis, Ulcerative

Intervention / Treatment
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* Drug: placebo
* Drug: MultiStem low dose
* Drug: placebo
* Drug: MultiStem low dose
* Drug: placebo
* Drug: MultiStem high dose
* Drug: placebo
* Drug: MultiStem high dose
* Drug: placebo
* Drug: MultiStem high dose
* Drug: placebo
* Drug: MultiStem high dose


Participation Criteria
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Eligibility Criteria
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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. Subjects must be on stable steroid doses. 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.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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). | Drug: placebo<br>* once every 7 days for 1- 3 doses<br>Drug: MultiStem low dose<br>* 1-3 doses<br>Drug: placebo<br>* Single dose at week 8<br>Drug: MultiStem low dose<br>* Single dose at week 8<br>|
| Experimental: Cohort 2<br>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. | Drug: placebo<br>* Single dose Day 1<br>Drug: MultiStem high dose<br>* Single dose Day 1<br>Drug: placebo<br>* Single dose at week 8<br>Drug: MultiStem high dose<br>* Single dose at week 8<br>|
| Experimental: Cohort 3<br>These subjects (total n=88 evaluable patients) 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. | Drug: placebo<br>* Single dose Day 1<br>Drug: MultiStem high dose<br>* Single dose Day 1<br>Drug: placebo<br>* Single dose at week 8<br>Drug: MultiStem high dose<br>* Single dose at week 8<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Endoscopic Score (as Measured by Modified Baron Score) at Week 8 | Modified Baron Score is an instrument designed to measure endoscopic activity of ulcerative colitis. It classifies the mucosal inflammation in 4 grades (0=normal, 1=granular mucosa with an abnormal vascular pattern, 2=friable mucosa, 3=microulceration with spontaneous bleeding, 4=gross ulceration with spontaneous bleeding). | Baseline and Week 8 | 
| Change From Baseline in Rectal Bleeding Mayo Subscore at Week 4 | Mayo Score is an instrument designed to measure disease activity of ulcerative colitis. Mayo subscores for rectal bleeding range from 0 to 3, with higher scores indicating more severe disease. | Baseline and Week 4 | 
| Change From Baseline in Rectal Bleeding Mayo Subscore at Week 8 | Mayo Score is an instrument designed to measure disease activity of ulcerative colitis. Mayo subscores for rectal bleeding range from 0 to 3, with higher scores indicating more severe disease. | Baseline and Week 8 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs. | Baseline up to Week 52 | 
| Number of Participants With Treatment-Emergent AEs by System Organ Class (SOC) |  | Baseline up to Week 52 | 
| Number of Treatment-Emergent AEs by Severity | The intensity grades were defined as follows: mild=does not interfere with participant's usual function; moderate=interferes to some extent with participant's usual function; severe=interferes significantly with participant's usual function. | Baseline up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Rectal Bleeding Mayo Subscore at Week 12 and Week 16 | Mayo Score is an instrument designed to measure disease activity of ulcerative colitis. Mayo subscores for rectal bleeding range from 0 to 3, with higher scores indicating more severe disease. | Baseline, Week 12, Week 16 | 
| Number of Participants With Laboratory Test Abnormalities | The total number of participants with laboratory test abnormalities with or without regard to baseline abnormality was assessed. Laboratory parameters included: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, platelet count, white blood cell [WBC] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes, erythrocyte sedimentation rate); chemistry (blood urea nitrogen and creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid, albumin, total protein; urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, microscopy (only if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase); other (follicle-stimulating hormone, human chorionic gonadotropin, stool microbiology, creatinine kinase, direct bilirubin, indirect bilirubin, gamma-glutamyl transferase, international normalized ratio. | Baseline up to Week 24 | 
| Number of Participants With Potentially Clinically Significant Vital Signs Findings | Vital signs assessment included pulse rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP). Criteria for vital sign values meeting potential clinical concern included: SBP <90 millimeters of mercury (mm Hg) and >=30 mm Hg increase/decrease from baseline, DBP <50 mm Hg and >=20 mm Hg increase/decrease from baseline, pulse rate <40 or >120 beats per minute (bpm), | Baseline up to Week 52 | 
| Fold Change From Baseline in Fecal Calprotectin at Weeks 4, 8, 12, and 16 | Fecal calprotectin, a very stable marker, is a 36kDa calcium and zinc binding protein which is neutrophil-derived. It represents 60% of cytosolic proteins in granulocytes and is a measurement of neutrophil migration to the gastrointestinal tract. | Baseline, Weeks 4, 8, 12 and 16 | 
| Fold Change From Baseline in C-Reactive Protein (CRP) at Weeks 4, 8, 12, and 16 | CRP is an acute-phase protein which provides an objective criterion of inflammatory activity. CRP has a short half-life (19 hours) and therefore rises early after the onset of inflammation and rapidly decreases after resolution of the inflammation. It is induced by interleukin-6, TNF-alpha and other pro-inflammatory cytokines that are produced within the intestinal lamina propria. | Baseline, Weeks 4, 8, 12 and 16 | 
| Percentage of Participants With Rectal Bleeding Mayo Subscore of Zero at Weeks 4, 8, 12, and 16 | Mayo subscores for rectal bleeding range from 0 to 3 (0=no blood seen; 1=streaks of blood with stool less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes). | Week 4, 8, 12 and 16 | 
| Percentage of Participants in Endoscopic Remission at Week 8 | Modified Baron Score is an instrument designed to measure endoscopic activity of ulcerative colitis. It classifies the mucosal inflammation in 4 grades (0=normal, 1=granular mucosa with an abnormal vascular pattern, 2=friable mucosa, 3=microulceration with spontaneous bleeding, 4=gross ulceration with spontaneous bleeding). Endoscopic remission is defined as modified Baron Endoscopic Score equal to 0. | Week 8 | 
| Percentage of Participants in Clinical Remission at Week 8 | Clinical remission is defined as a total Mayo score of 2 points or lower, with no individual subscores exceeding 1 point. | Week 8 | 
| Percentage of Participants With Decrease From Baseline of at Least 1 Point in Rectal Bleeding Mayo Subscore at Weeks 4, 8, 12, and 16 | Mayo subscores for rectal bleeding range from 0 to 3 (0=no blood seen; 1=streaks of blood with stool less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes). A decrease from baseline score indicates improvement. | Baseline, Weeks 4, 8, 12 and 16 | 
| Percentage of Participants With Endoscopic Response at Week 8 | Endoscopic response is defined as a decrease in modified Baron endoscopic score from baseline of at least 2 points. | Week 8 | 
| Percentage of Participants in Clinical Response at Week 8 | Clinical response is defined as a decrease in total Mayo score from baseline of at least 3 points and at least 30 percent (%), with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. | Week 8 | 
| Change From Baseline in Total Mayo Scores at Week 8 | Mayo Score is an instrument designed to measure disease activity of ulcerative colitis, with total score ranging from 0 to 12. It consists of 4 subscores (stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy, and physician global assessment [PGA]), each graded from 0 to 3, with higher scores indicating more severe disease. | Baseline, Week 8 | 
| Change From Baseline in Partial Mayo Scores at Weeks 4, 8, 12, and 16 | Mayo Score is an instrument designed to measure disease activity of ulcerative colitis. Mayo Score ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease. A Partial Mayo Score (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and PGA) with each ranging from 0 to 3 (0=normal, 1=mild, 2=moderate, 3=severe). Higher scores indicate more severe disease. | Baseline, Weeks 4, 8, 12 and 16 | 
| Change From Baseline in Biopsy Histology Scores at Week 8 | A 15 to 25 centimeter (cm) biopsy sample of inflamed mucosal tissue was taken from the worst affected area and scored using the Riley Index. The Riley Index is a histologic scoring system for the assessment of the activity and severity of ulcerative colitis, ranging from 0 to 24. It consists of 6 histologic features (acute inflammatory cell infiltrate, crypt abscesses, mucin depletion, surface epithelial integrity, chronic inflammatory cell infiltrate, and crypt architectural irregularities), all scored on a 4-point scale (higher scores indicate more severe disease). | Baseline and Week 8 | 
| Change From Baseline in Patient-Reported Rectal Bleeding up to Week 16 | Patient-reported diary data assessed the number of bowel movements (BM) per day when not having a flare and the presence of blood in the stools (rectal bleeding [RB]), if any. | Baseline and Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety efficacy MultiStem(r) moderate to severe Ulcerative Colitis