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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
DigestScience
Information provided by (Responsible Party):
HeinVerspaget, Leiden University Medical Center
ClinicalTrials.gov Identifier:
NCT01144962
First received: June 14, 2010
Last updated: July 4, 2014
Last verified: July 2014
  Purpose

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).


Condition Intervention Phase
Crohn's Disease
Fistula
Procedure: Localization, curettage of the fistulous tract and closure of the internal opening without MSC injection.
Procedure: Localization, curettage of the fistulous tract and closure of the internal opening with local MSC injection.
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Allogeneic Bone Marrow Derived Mesenchymal Stem Cells for the Treatment of Fistulas in Patients With Refractory Perianal Crohn's Disease

Resource links provided by NLM:


Further study details as provided by Leiden University Medical Center:

Primary Outcome Measures:
  • Safety and efficacy (fistula closure) [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    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).


Secondary Outcome Measures:
  • Clinical scores [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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;

  • Endoscopic scores [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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);

  • Quality of life [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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;

  • C-reactive protein (CRP) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    4. To summarize the changes from baseline compared to 12 weeks in serum C-reactive protein (CRP).

  • Safety [ Time Frame: 12 and 24 weeks ] [ Designated as safety issue: Yes ]
    5. To assess the incidence of surgical intervention and infections.


Estimated Enrollment: 21
Study Start Date: June 2010
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Procedure: Localization, curettage of the fistulous tract and closure of the internal opening without MSC injection.
Patients will undergo surgical localization, curettage of the fistulous tract and closure of the internal opening, without injection of MSCs.
Active Comparator: Cohort 1
10x10^6 MSC
Procedure: Localization, curettage of the fistulous tract and closure of the internal opening with local MSC injection.
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
Procedure: Localization, curettage of the fistulous tract and closure of the internal opening with local MSC injection.
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
Procedure: Localization, curettage of the fistulous tract and closure of the internal opening with local MSC injection.
Patients will undergo surgical localization, curettage of the fistulous tract and closure of the internal opening, with local injection of indicated dose of MSCs

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01144962

Locations
Netherlands
Leiden University Medical Center (LUMC)
Leiden, Zuid Holland, Netherlands, 2333 ZA
Sponsors and Collaborators
Leiden University Medical Center
DigestScience
Investigators
Principal Investigator: Daniel W Hommes, MD PhD Leiden University Medical Center (LUMC)
  More Information

No publications provided

Responsible Party: HeinVerspaget, Associate Professor, Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT01144962     History of Changes
Other Study ID Numbers: P10.102
Study First Received: June 14, 2010
Last Updated: July 4, 2014
Health Authority: Netherlands: Ministry of Health, Welfare and Sport

Keywords provided by Leiden University Medical Center:
Crohn's Disease
Fistula
Mesenchymal Stem Cell
Mesenchymal Stromal Cell
MSC
IBD

Additional relevant MeSH terms:
Crohn Disease
Fistula
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Pathological Conditions, Anatomical

ClinicalTrials.gov processed this record on August 21, 2014