| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Ulcerative Colitis is a type of Inflammatory Bowel Disease (IBD), which involves inflammation of all or part of the colon. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the safety and tolerability of intravenous doses of MultiStem in moderate-to-severe ulcerative colitis.
• To study the efficacy of a single intravenous dose of MultiStem in moderate-to-severe ulcerative colitis measured by an effect on endoscopic and rectal bleeding scores.
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| E.2.2 | Secondary objectives of the trial |
• To study the effect of a single intravenous dose of MultiStem on disease severity measured by total and partial Mayo score.
• To study the effect of repeat intravenous dose of MultiStem on disease measured by partial Mayo score and by rectal bleeding.
• To study the effect of intravenous doses of MultiStem on fecal calprotectin and C-reactive protein (CRP) levels. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study. The selection of patients is based on the data available from Screening. Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1.Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, lifestyle guidelines and other study procedures.
3. Subject must be at least 18 years of age.
4. Males and females with a documented diagnosis (endoscopic or radiographic) of UC ≥6 months prior to screening.
5. For Cohort 1 and 2 only: Active moderate-to-severe UC defined as Mayo score of ≥6 and <11.
6. For Cohort 3 only: Active moderate-to-severe UC defined as Mayo score of ≥6.
7. Modified Baron endoscopic score of ≥2 determined within 21 days of first dosing for Cohort 1 and within 7 days of first dosing for Cohorts 2 and 3 (flexible sigmoidoscopy unless surveillance colonoscopy clinically indicated).
8. 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.
9. Subjects currently receiving the following treatment regimens for UC are eligible providing they are on stable dose for designated period of time:
a. 5-ASA or sulfasalazine stable dose for at least 3 weeks prior to Day 1 and during the study treatment period.
b. Corticosteroids or equivalent at a stable dose for at least 2 weeks prior to Day 1 study visit (Prednisolone ≤25 mg/day, or equivalent). NOTE: Tapering of corticosteroids or equivalent may only commence at Week 8 (see “Concomitant Medications” section of the protocol).
c. Antibiotics (eg, metronidazole, rifaximin) stable dose for at least 2 weeks prior to Day 1 study visit and during the study treatment period ie, up to Week 8.
d. Rectally administered formulation of corticosteroids or 5-ASA stable dose for at least 2 weeks prior to Day 1 study visit and during the study treatment period i.e. up to Week 8.
e. Methotrexate (up to 15 mg/week subcutaneously), azathioprine (up to 2.5 mg/kg/day) and 6-mercaptopurine (up to 1.5 mg/kg/day) stable for at least 2 months prior to Day 1 study visit and during the study treatment period i.e. up to Week 8. NOTE: excluded medications include anti-TNF therapies used within 8 weeks of Day 1 study visit or cyclosporine, mycophenolate, or tacrolimus used within 4 weeks of Day 1 study visit as described in the exclusion criteria.
10.Subjects willing to use double contraception during the study treatment period and until completion of follow-up procedures ie, Week 52: (a) If the subject is a sexually active woman of childbearing potential, she and her male partner are required to simultaneously use 2 effective contraceptive methods as listed in Section 4.4.2 of the protocol. Female subjects who wish to use non-hormonal contraception must have done so for at least 14 days prior to the Day 1 study visit. (b) Non-vasectomized males with female partners of child bearing potential must be willing to use a condom in addition to having their female partner use another form of contraception as listed in Section 4.4.2. of the protocol.
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. Subjects who are investigational site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial.
2. Abnormal organ and marrow function as defined: (a) leukocytes <4,000/µL. (b) Platelets <150,000/µL. (c) AST (SGOT) or ALT (SGPT) >3x institutional upper limit of normal. (d) Bilirubin >upper institutional limit of normal. (e) Creatinine >1.2 mg/dL.
3. Diagnosis of indeterminate colitis, or clinical findings suggestive of Crohn’s disease, including Crohn’s enterocolitis, ischaemic colitis, radiation colitis, diverticular disease associated colitis as well as microscopic colitis.
4. Subjects with UC, which is confined to a proctitis defined as inflammation limited to less than 15 cm from the anal verge on a flexible sigmoidoscopy.
5. Subjects who meet Truelove-Witts criteria for severe UC. Diarrhea >6 times/day, bloody and any one of the items: (a) Hemoglobin 75% or below of normal value. (b) Evening temperature >37.5◦C. (c) Pulse rate >90 beats/min. (d) ESR >30 mm/h.
6. Subjects who have received i.v. steroids or TPN or have been hospitalized due to UC within 3 weeks prior to screening.
7. Subjects displaying clinical signs of toxic megacolon, ischemic colitis or fulminant colitis.
8. Known allergies to bovine or porcine products, dextran or H1 blockers.
9. 9. Known intolerance to corticosteroids.
10. Subjects who have previously participated in any study of an allogeneic cell therapy, with the exception of erythrocyte transfusions.
11. Subjects who have received any investigational drug or device within 3 months (or as determined by the local requirement, whichever is longer) prior to Day 1 study visit.
12. History of symptomatic obstructive strictures, an ostomy, extensive bowel resection
(>100 cm) or short bowel syndrome.
13. History of bowel surgery within 6 months prior to Day 1 study visit.
14. Subject who have had surgery as a treatment for UC or, in the opinion of the investigator, are likely to require surgery within 16 weeks of informed consent.
15. Subjects diagnosed with primary sclerosing cholangitis.
16. Subjects with active inflammatory eye disease.
17. Subjects with spondylarthropathy and active musculoskeletal manifestation.
18. Subjects with active pyoderma gangrenosum or erythema nodosum lesions.
19. Subjects with clinically significant pulmonary disease (eg, subjects with COPD GOLD stage III or IV).
20. Subjects with NYHA class IV congestive heart failure.
21. Subjects with active systemic or severe local infections.
22. Fecal culture indicating presence of pathogenic infection; positive C. difficile toxin, or positive stool ova and parasite exam.
23. Subjects likely to require any type of surgery within 16 weeks from informed consent.
24. Known collection or abscess on MRI of the pelvis.
25. Pregnant or lactating women.
26. History of alcohol or drug abuse with less than 6 months of abstinence prior to Day 1 study visit.
27. Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results.
28. Subjects with a temperature of 38◦C (100.4◦F) or higher at screening.
29. Subjects with malignancies or with a history of malignancies with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin.
30. Significant trauma or major surgery within 4 weeks of screening visit.
31. Subjects infected with human immunodeficiency virus (HIV) or hepatitis B or C viruses.
32. Subjects receiving or who are expected to receive concomitant medications in the list of prohibited medications. (a) Infliximab or other biologic treatment within 8 weeks of the Day 1 study visit. (b) Cyclosporine, mycophenolate, or tacrolimus within 4 weeks of the Day 1 study visit.
33.Subjects who, in the opinion of the investigator or Pfizer, will be uncooperative or unable to comply with study procedures.
34.Subjects participating in another ongoing clinical study.
35. Any other condition which would make the subject unsuitable for inclusion in the study.
36. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
37.Unwilling or unable to comply with the Lifestyle guidelines described in this protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Incidence and severity of adverse events (at Weeks, 4, 8, 12 and 16).
- Change from baseline of endoscopic score at Week 8 as measured by modified Baron score.
- Change from baseline of Mayo rectal bleeding sub-score at Week 4.
- Change from baseline of Mayo rectal bleeding sub-score at Week 8.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Change from baseline of Mayo rectal bleeding sub-score at Weeks 12 and 16.
• Changes in laboratory measurements of safety and vital signs (at Weeks 4, 8, 12, and 16).
• Changes from baseline at Weeks 4, 8, 12 and 16 in the following biomarker levels: fecal calprotectin, CRP.
• Proportion of subjects with a Mayo rectal bleeding sub-score equal 0 at Weeks 4, 8, 12 and 16.
• Proportion of subjects in endoscopic remission at Week 8 (defined as subjects with a modified Baron endoscopic score equal 0).
• Proportions 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).
• 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.
• 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).
• 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 1 point or an absolute sub-score for rectal bleeding of 0 or 1).
• Changes from baseline in total Mayo score at Week 8.
• Changes from baseline in partial Mayo score at Weeks 4, 8, 12 and 16.
• Patient-reported rectal bleeding scores, to be modeled longitudinally up to and including Week 16.
• Changes in biopsy histology score at Week 8 (measured by Riley Index). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Germany |
| Hungary |
| Italy |
| Poland |
| Slovakia |
| Sweden |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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