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

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

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.

Study Overview

• Status: Completed
• Conditions: Colitis, Ulcerative
• Intervention / Treatment: Drug: placebo; Drug: MultiStem low dose; Drug: placebo; Drug: MultiStem low dose; Drug: placebo; Drug: MultiStem high dose; Drug: MultiStem high dose

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • Hopital Erasme / Gastroenterology
  • Bruxelles, Belgium, 1070
    • Pfizer Clinical Research Unit
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
    • Edmonton, Alberta, Canada, T6G 2X8
      • Zeidler Ledcor Centre - University of Alberta
    • Edmonton, Alberta, Canada, T6G 2C8
      • Northern Alberta Clinical Trials and Research Center
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Maisonneuve-Rosemont Hospital
• Germany
  • Frankfurt am Main, Germany, 60431
    • Agaplesion Markus Krankenhaus
  • Halle, Germany, 06120
    • Universitaetsklinikum Halle
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
• Hungary
  • Budapest, Hungary, 1125
    • Szent Janos Korhaz es Eszak-budai Egyesitett Korhazak/I. Belgyogyaszat es Gastroenterologia
  • Gyula, Hungary, 5700
    • Pandy Kalman Megyei Korhaz, III. sz. Belosztaly-Gasztroenterologia
  • Mosonmagyarovar, Hungary, 9200
    • Karolina Korhaz Rendelointezet, Belgyogyaszat
  • Szekszard, Hungary, 7100
    • Tolna Megyei Balassa Janos Korhaz / II. Belgyogyaszat
• Italy
  • Milano, Italy, 20157
    • Azienda Ospedaliera Luigi Sacco
  • Padova, Italy, 35128
    • Azienda Ospedaliera di Padova
  • Roma, Italy, 00168
    • Policlinico Universitario Agostino Gemelli
• Slovakia
  • Bratislava, Slovakia, 826 06
    • Gastroenterologicke a hepatologicke oddelenie, V. interna klinika LFUK a UN Bratislava, Ruzinov
  • Trnava, Slovakia, 917 01
    • Gastroenterologicka ambulancia, GEA s.r.o.
• Sweden
  • Goteborg, Sweden, 413 45
    • Sahlgrenska Universitetssjukhuset Medicinkliniken
  • Stockholm, Sweden, 171 76
    • Karolinska Universitetssjukhuset, GastroCentrum Medicin
  • Uppsala, Sweden, 751 85
    • Akademiska sjukhuset, Mag tarmmottagningen
• United States
  • California
    • San Francisco, California, United States, 94115
      • University of California San Francisco
    • San Francisco, California, United States, 94115
      • USCF Endoscopy Unit at Mount Zion
  • Colorado
    • Lafayette, Colorado, United States, 80026
      • Clinical Research of the Rockies
    • Lakewood, Colorado, United States, 80215
      • Rocky Mountain Gastroenterology Associates, LLC
    • Littleton, Colorado, United States, 80120
      • Arapahoe Gastroenterology, PC
  • District of Columbia
    • Washington, District of Columbia, United States, 20006
      • Metropolitan Gastroenterology Group, PC
  • Florida
    • Clearwater, Florida, United States, 33765
      • Clinical Research of West Florida, Inc.
    • Clearwater, Florida, United States, 33756
      • West Coast Endoscopy Center
    • Clearwater, Florida, United States, 33756
      • Gastroenterology Consultants of Clearwater
    • Jacksonville, Florida, United States, 32256
      • Borland-Groover Clinic
    • Jacksonville, Florida, United States, 32256
      • Jacksonville Center for Endoscopy
    • South Miami, Florida, United States, 33143
      • Miami Research Associates
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Cotton-O'Neil Clinical Research Center, Digestive Health
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Hospital
    • Louisville, Kentucky, United States, 40202
      • University Of Louisville Healthcare Outpatient Center
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Metropolitan Gastroenterology Group, PC - Chevy Chase Clinical Research
    • Towson, Maryland, United States, 21204
      • Endoscopic Microsurgery Associates, PA
  • Michigan
    • Chesterfield, Michigan, United States, 48047
      • Clinical Research Institute of Michigan, LLC
    • Troy, Michigan, United States, 48098
      • Center for Digestive Health
    • Utica, Michigan, United States, 48317
      • Utica Surgery Center
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Surgery Center of Columbia
    • Mexico, Missouri, United States, 65265
      • Center for Digestive and Liver Diseases, Inc.
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10028
      • Present, Chapman, Steinlauf and Marion
    • New York, New York, United States, 10128
      • Asher Kornbluth, MD PC
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Charlotte Gastroenterology and Hepatology, PLLC
    • Raleigh, North Carolina, United States, 27612
      • Wake Research Associates
    • Raleigh, North Carolina, United States, 27612
      • Wake Internal Medicine Consultants, Inc.
    • Winston Salem, North Carolina, United States, 27157
      • Wake Forest University University Baptist Medical Center - Internal Medicine
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Gastro One
    • Nashville, Tennessee, United States, 37232-1375
      • Vanderbilt University Medical Center
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital
    • Norfolk, Virginia, United States, 23502
      • Digestive and Liver Disease Specialists
    • Norfolk, Virginia, United States, 23502
      • Sentara Leigh Hospital
    • Richmond, Virginia, United States, 23249
      • McGuire DVAMC
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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).	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
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.	Drug: placebo; once every 7 days for 1- 3 doses; Drug: placebo; 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 3; 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; once every 7 days for 1- 3 doses; Drug: placebo; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Athersys, Inc

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: November 10, 2010
• First Submitted That Met QC Criteria: November 10, 2010
• First Posted (Estimate): November 15, 2010

Study Record Updates

• Last Update Posted (Estimate): February 23, 2016
• Last Update Submitted That Met QC Criteria: January 26, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: safety efficacy MultiStem(r) moderate to severe Ulcerative Colitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: B3041001; 2010-022766-27 (EudraCT Number)