In a dose escalation study we will determine the safety and preliminary efficacy of allogeneic bmMSCs in the induction of response for active fistulizing CD.
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. To assess the safety (incidence of intervention related [serious] adverse
events) and tolerability of the surgical intervention alone or the surgical
intervent with local administration of different doses of allogeneic MSCs in
fistula tracts of patients with refractory CD.
2. To document the efficacy of different doses of allogeneic bmMSCs in the
induction of response for active fistulizing CD.
Secondary outcome
At 12 weeks
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 MSC treatment;
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);
3. To evaluate the effect of local treatment with autologous bmMSCs on the
quality of life of patients with fistulizing CD using the Inflammatory Bowel
Disease Questionnaire (IBDQ) and Short Form (SF)-36 score;
4. To summarize the changes from baseline compared to 12 weeks in serum CRP.
At 12 and 24 weeks
5. To assess the incidence of surgical intervention and infections.
Background summary
Despite the introduction of anti-TNF 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 MSCs (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.
Study objective
In a dose escalation study we will determine the safety and preliminary
efficacy of allogeneic bmMSCs in the induction of response for active
fistulizing CD.
Study design
This is a prospective, dose-escalating therapeutic exploratory study.
Intervention
MSC implantation will be preceded by surgical localization, curettage of the
fistulous tract and closure of the internal opening. 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).
Study burden and risks
Crohn's Disease is a severe disorder with significant morbidity and impact on
quality of life.
Perianal fistulas lead to substantial physical and emotional distress because
of pain, discharge, incontinence, perianal and genital disfigurement, and slow
resolution even with treatment.
Promising results have been seen in studies on intravenous MSC administration
in patients with severe steroid resistant Graft versus Host Disease69,
including GvHD of the gut. These data is supported by encouraging results from
studies with locally administered adipose tissue derived MSCs to treat complex
perianal fistula in Crohn*s disease. Patients who can participate in this study
have debilitating fistulizing disease not responding to medical therapy and
other therapeutic options are limited. We think that these results, which
suggest a beneficial effect from MSC administration for patients with
fistulizing CD, and the expected limited possibility on adverse side effects,
justify participation in this study.
Albinusdreef 2
2333 ZA Leiden
NL
Albinusdreef 2
2333 ZA Leiden
NL
Listed location countries
Age
Inclusion criteria
a) Men and women of at least 18 years of age;
b) 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;
c) CDAI score of <250 at screening and baseline;
d) 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, methotrexate, or infliximab) which did not result in an adequate response to treatment;
e) 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
f) Patients included in the study might be receiving 5-aminosalicylic acid (5-ASA), steroids, azathioprine, 6-mercaptopurine (6-MP), methotrexate, infliximab or any similar drug at the time of enrolment, 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 enrolment.
The dose of steroids must be stable for at least 4 weeks prior to enrolment.
The dose of immunosuppressants (for example azathioprine, 6MP, or methotrexate) must have been stable for at least 8 weeks prior to enrolment and the patient on therapy for at least three months prior to enrolment.
The dose of infliximab or other anti-TNF drug must have been stable for at least 8 weeks prior to enrolment;
g) No need for immediate surgery (obstruction, strictures or abscess);
h) If female and of child-bearing age, patient must be non-pregnant, non-breastfeeding, and use adequate contraception;
i) 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
a) Patients with evidence of acute peri-anal infection, presence of peri-anal abscesses larger than 2 cm, and anal or rectal stricture;
b) Patients with evidence of any infections needing antibiotic treatment.
c) Rectovaginal fistulas, or complex peri-anal fistulas with more than two internal openings;
d) Patients suffering from renal- or hepatic failure.
e) Use of any investigational drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer;
f) Patient is allergic to gadolinium (MRI contrast agent);
g) 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);
h) 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
i)Change in concomitant medication:
*Steroids must be stable for at least 4 weeks prior to enrolment,
*5-ASA should be on a stable dose > 4 weeks prior to enrolment,
*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 be on a stable dose > 8 weeks prior to enrolment.
j) Clausterphobia;
k) Documented HIV infection. Active hepatitis B, hepatitis C or TB;
l) 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;
m) 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;
n) 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);
o) History of lymphoproliferative disease including lymphoma;
p) Patient is unwilling or unable to comply with the study procedures.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-015680-14-NL |
| ClinicalTrials.gov | NCT01144962 |
| CCMO | NL29565.000.10 |