Dose-escalating Therapeutic Study of Allogeneic Bone Marrow Derived Mesenchymal Stem Cells for the Treatment of Fistulas in Patients With Refractory Perianal Crohn's Disease
December 29, 2014 updated by: HeinVerspaget, Leiden University Medical Center
Allogeneic Bone Marrow Derived Mesenchymal Stem Cells for the Treatment of Fistulas in Patients With Refractory Perianal Crohn's Disease
In a dose escalation study we will determine the safety and preliminary efficacy of allogeneic bone marrow mesenchymal stem cells (bmMSCs) in the induction of response for active fistulizing Crohn's Disease (CD).
Study Overview
Status
Completed
Conditions
Detailed Description
Despite the introduction of anti-TNFa (tumor necrosis factor alpha) therapy, perianal disease still accounts for a high rate of morbidity in patients diagnosed with CD. Recently, a phase II multicenter randomized study was reported showing that expanded adipose tissue derived mesenchymal stem cells (atMSCs) in combination with fibrin glue was an effective and safe treatment for complex perianal fistula. However, dose escalation of allogeneic bone marrow (bm) MSCs for the local treatment of perianal fistulas has not been studied.
In this study, three escalating doses will be tested in a total of three cohorts. MSC implantation will be preceded by surgical localization, curettage of the fistulous tract and closure of the internal opening. Per cohort, patients will be randomized in a 5:2 fashion to receive either 10x10^6 (cohort 1), 30x10^6 (cohort 2) or 90x10^6 (cohort 3) bmMSCs or no cells (control group).
The primary endpoint will be assessed at week 12: i) the number of adverse and serious adverse events and ii) a reduction in the number of draining fistulas, which is defined as absence of discharge and absence of collections of ≥2 cm directly related to the treated fistulas tracts as measured by MRI.
Study Type
Interventional
Enrollment (Actual)
21
Phase
- Phase 2
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
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Zuid Holland
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Leiden, Zuid Holland, Netherlands, 2333 ZA
- Leiden University Medical Center (LUMC)
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
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:
- Men and women > 18 years of age
- Patient must have had CD (for at least 3 months from the time of initial diagnosis). The diagnosis of CD must have been confirmed by endoscopic and histologic evidence
- CDAI score of <250 at screening and baseline
- Peri-anal fistulas must be refractory to conventional medical therapy Which means that at some time during the course of the disease, patient must have received both steroids and immunosuppressive agents (for example, azathioprine, 6-mercaptopurine (6-MP), methotrexate, or infliximab) which did not result in an adequate response to treatment
- Patients with previous surgical attempts to eradicate perianal fistulas are eligible for inclusion as are patients with setons in situ. Setons will be removed during the surgical procedure
- Patients included in the study might be receiving 5-aminosalicylic acid (5-ASA), steroids, azathioprine, 6-MP, methotrexate, or any similar drug at the time of enrolment and is allowed to have a history of infliximab treatment, provided the following conditions are fulfilled at screening:
- The dose of 5-ASA (both oral and rectal) must have been stable for at least 4 weeks prior to enrollment
- The dose of steroids must be stable for at least 4 weeks prior to enrollment
- The dose of immunosuppressants (for example azathioprine, 6-MP, or methotrexate) must have been stable for at least 8 weeks prior to enrollment and the patient on therapy for at least three months prior to enrollment
- The last dose of infliximab or other anti-TNF drug is > 8 weeks prior to enrollment
- No need for immediate surgery (obstruction, strictures or abscess)
- If female and of child-bearing age, patient must be non-pregnant non-breastfeeding, and use adequate contraception
- Patient is willing to participate in the study and has signed the informed consent. Consent must be obtained prior to any study procedure
Exclusion Criteria:
- Patients with evidence of acute peri-anal infection, presence of peri-anal abscesses larger than 2 cm, and anal or rectal stricture
- Patients with evidence of any infections needing antibiotic treatment
- Rectovaginal fistulas, or complex peri-anal fistulas with more than two internal openings
- Patients suffering from renal- or hepatic failure
- Use of any investigational drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer
- Patient is allergic to gadolinium (MRI contrast agent)
- Patient with severe renal insufficiency defined as patients with a glomerular filtration rate (GFR) below 60 mL/min/1.73 m2. GFR = 186.3 x (serum creatinine)-1.154 x (age in years)-0.203 x 1.212 (if patient is black) x 0.742 (if female)
Due to the high strength electromagnetic fields that will be used during MRI there is a risk of interference with any metallic implants in the body. The following conditions will disqualify patients from having an MRI and will be excluded from this study:
- Electronically, magnetically, and mechanically activated implants
- Ferromagnetic or electronically operated stapedial implants
- Cardiac pacemakers/carotid sinus pacemaker implant
- Hemostatic clips
- Metallic splinters in the orbit
- Insulin pumps and nerve stimulators
- Lead wires or similar wires
- Metal intrauterine device
Change in concomitant medication:
- Steroids must be stable for at least 4 weeks prior to enrollment
- 5-ASA should be on a stable dose > 4 weeks prior to enrollment
- Immunosuppressants (e.g. azathioprine, 6MP or methotrexate) should be on a stable dose > 8 weeks prior to enrolment
- Infliximab or other anti-TNF antibody therapy should not be administered < 8 weeks prior to enrollment
- Claustrophobia
- Documented HIV (Human Immunodeficiency Virus) infection. Active hepatitis B, hepatitis C or TB
- Patients who currently have or who have had an opportunistic infection (e.g., herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 6 months prior to screening
- Serious infections (such as pneumonia or pyelonephritis) in the previous 3 months. Less serious infections (such as acute upper respiratory tract infection [colds] or simple urinary tract infection) need not be considered exclusions at the discretion of the investigator
- Malignancy within the past 5 years (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence)
- History of lymphoproliferative disease including lymphoma
- Patient is unwilling or unable to comply with the study procedures
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Sham Comparator: Control group
Patients in the control group will undergo surgical localization, curettage of the fistulous tract and closure of the internal opening, without injection of MSCs.
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Patients will undergo surgical localization, curettage of the fistulous tract and closure of the internal opening, without injection of MSCs.
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|
Active Comparator: Cohort 1
10x10^6 MSC
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Patients will undergo surgical localization, curettage of the fistulous tract and closure of the internal opening, with local injection of indicated dose of MSCs
|
|
Active Comparator: Cohort 2
30x10^6 MSC
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Patients will undergo surgical localization, curettage of the fistulous tract and closure of the internal opening, with local injection of indicated dose of MSCs
|
|
Active Comparator: Cohort 3
90x10^6 MSC
|
Patients will undergo surgical localization, curettage of the fistulous tract and closure of the internal opening, with local injection of indicated dose of MSCs
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Safety and efficacy (fistula closure)
Time Frame: 12 weeks
|
i) the number of adverse and serious adverse events and ii) a reduction in the number of draining fistulas, which is defined as absence of discharge and absence of collections of ≥2 cm directly related to the treated fistulas tracts as measured by MRI (Magnetic Resonance Imaging).
|
12 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Clinical scores
Time Frame: 12 weeks
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1. To assess changes in the Crohn's Disease Activity Index (CDAI), the Perianal Disease Activity Index (PDAI) and the adapted Vaizey fecal incontinence score before and after mesenchymal stem cell (MSC) treatment;
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12 weeks
|
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Endoscopic scores
Time Frame: 12 weeks
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2. To compare endoscopic changes before and after local bmMSC treatment using the Crohn's Disease Endoscopic Index of Severity (CDEIS) and simplified endoscopic activity score for Crohn's disease (SES-CD);
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12 weeks
|
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Quality of life
Time Frame: 12 weeks
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3. To evaluate the effect of local treatment with autologous bmMSCs on the quality of life of patients with fistulizing CD using the short Inflammatory Bowel Disease Questionnaire (sIBDQ) and Short Form (SF)-36 score;
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12 weeks
|
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C-reactive protein (CRP)
Time Frame: 12 weeks
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4. To summarize the changes from baseline compared to 12 weeks in serum C-reactive protein (CRP).
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12 weeks
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Safety
Time Frame: 12 and 24 weeks
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5. To assess the incidence of surgical intervention and infections.
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12 and 24 weeks
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Study Chair: Hein W Verspaget, PhD, Leiden University Medical Center (LUMC)
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
June 1, 2010
Primary Completion (Actual)
September 1, 2014
Study Completion (Actual)
December 1, 2014
Study Registration Dates
First Submitted
June 14, 2010
First Submitted That Met QC Criteria
June 15, 2010
First Posted (Estimate)
June 16, 2010
Study Record Updates
Last Update Posted (Estimate)
December 30, 2014
Last Update Submitted That Met QC Criteria
December 29, 2014
Last Verified
December 1, 2014
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- P10.102
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