The primary objective of the study is to evaluate the efficacy of intralesional administration of eASCs (CX-401) when added to standard surgical care and drainage for the treatment of complex perianal fistulas in patients with Crohn*s disease (CD…
ID
Source
Brief title
Condition
- Gastrointestinal stenosis and obstruction
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the percentage of anti-TNF previous exposed patients
with complete closure of their treated complex perianal fistula at Week 24.
Complete closure of the fistula is defined as:
•Absence of drainage/suppuration of the fistula through the external orifice,
either spontaneously or when applying pressure, and
•Complete re-epithelization of the external orifice (clinical evaluation), and
•Absence of fluid collections >2 cm directly related to the treated fistula
tract, as measured by MRI, in the longest diameter.
Clinically, complete closure must be confirmed at both, the Week 24 and the
Week 26 visit.
Secondary outcome
Secondary:
•Changes over time in the PDAI and CDAI between baseline, Week 12 and Week 24
•Percentage of the complete set of patients with complete closure of their
treated complex perianal fistula at week 24. Clinically, complete closure must
be confirmed at the week 24 and the week 26 visit.
•Percentage of patients with complete closure of the treated complex perianal
fistula after 12 weeks of eASCs exposure. Clinically, complete closure must be
confirmed at the Week 10 and the Week 12 visit.
•Percentage of patients with MRI confirmed absence of collections >2 cm of the
treated perianal fistula at Weeks 12 and 24.
•Percentage of patients with exacerbation or relapse of CD at Weeks 12 and 24.
This is herewith defined any deterioration in the CDAI total score.
•Changes over time in the MRI Score of Severity (MSS) between baseline, Week 12
and Week 24.
•QoL as measured by SF-36 questionnaire.
•Percentage of patients for whom surgeries of the treated fistula could be
avoided.
Safety variables:
•Adverse events (AEs), serious adverse events (SAEs), signs, symptoms and
clinical diagnosis, surgeries.
•Clinically relevant variations in physical examination findings during the
study.
•Clinically relevant variations in vital signs during the study.
•Clinically relevant variations in laboratory data during the study.
Background summary
Crohn*s disease is a chronic inflammatory disease of the intestine of unknown
etiology. It is characterized by focal or segmental transmural inflammation
that can occur in any part of the digestive tract with occasional granuloma
formation.
The cumulative incidence of perianal fistulas in Crohn*s disease varies between
20% and 50% perianal disease is associated with high morbidity and, typically,
with local pain and discharge; it therefore has a very negative impact on the
quality of life of the affected Subjects.
Cell therapy based on stem cell technologies is rapidly being introduced in a
variety of areas of medicine, particularly since the introduction of adult stem
cells. This allows for autologous transplantation, thus avoiding
rejection-related issues and ethical concerns, such as those relative to
embryonic stem cells.
The purpose of this study is to examine the efficacy and safety of a new
therapy with expanded adipose derived stem cells (eASCs), in order to see if
subjects experience improvement in their disease symptoms and quality of life.
eASCs are thought to selectively affect the immune system to decrease
inflammation, typically increased in fistulizing disease and in doing so,
initiating tissue repair process, due to the natural repair properties of live
cells.
Study objective
The primary objective of the study is to evaluate the efficacy of intralesional
administration of eASCs (CX-401) when added to standard surgical care and
drainage for the treatment of complex perianal fistulas in patients with
Crohn*s disease (CD).
Study design
This is a phase III, multicenter, randomized, comparative, single-blind,
placebo-controlled study to evaluate the efficacy and safety of a new therapy
with eASCs for the treatment of complex perianal fistulas in patients with CD.
Both anti-TNF exposed patients (i.e. patients with previous anti-TNF therapy)
and anti-TNF naive patients (i.e. patients without previous anti-TNF therapy)
can be included. The recruitment will stop at the latest, when 156 anti-TNF
exposed patients have been randomized, i.e. no further patients (neither
anti-TNF exposed nor anti-TNF naive) will be enrolled into the screening period
after this time point, but patients already enrolled to the screening period at
this time point are allowed to continue and can be randomized, if they meet the
corresponding criteria. The recruitment might be stopped earlier, if a
sufficient number of anti-TNF exposed patients is in the screening period to
ensure a number of 156 randomized anti-TNF exposed patients.
Assuming a screening failure rate of 20%, about 198 anti-TNF exposed patients
will be screened. The screening failure rate will be monitored during the study
and the number of screened patients will be adapted as necessary to achieve a
number of 156 randomized anti-TNF exposed patients.
The number of screened anti-TNF naive patients will be restricted to at most
50. The percentage of anti-TNF naive patients is roughly estimated to be around
20%, which would result in about 40 randomized anti-TNF naive patients,
assuming the same screening failure rate of 20% as for the anti-TNF exposed
patients.
Each eligible patient will be randomized in a 1:1 ratio to receive either a
local intra-lesional injection eASCs in the fistula at a dose of 20 million
cells, or placebo. Patients must have had CD for a minimum of 12 months*
duration with a CD Activity Index (CDAI) score <220 scored over the 14 days
prior to the first treatment with CX-401.
All patients will undergo a baseline magnetic resonance imaging (MRI) to assess
the presence/absence of collections >2 cm associated to the fistula tract. All
study patients will undergo a liposuction to isolate autologuous stem cells
from the patients adipose tissue, in order to have an ASC bank available to be
used for treatment during the study.
Complete fistula closure will be clinically evaluated twice at two consecutive
visits (Weeks 10-12 as well as Weeks 24-26) by a blinded and unblinded
physician/surgeon. In addition, presence/absence of collections >2 cm
associated to the fistula tract will be radiologically evaluated by a blinded
radiologist at Weeks 12 and 24.
In case of incomplete/partial closure of the treated fistula at Week 12,
patients from the eASC group will receive a second dose of eASCs (40 million
cells). Patients in both treatment groups will be followed until Week 26.
Patients from both groups may be treated with standard of care (SOC) for CD
during the entire study period.
Patients from the placebo group with incomplete/partial fistula closure at Week
26 will be offered to participate in a separate open-label, single arm eASCs
protocol, as long as cells have been obtained from the patient within the scope
of this protocol.
Intervention
liposuction during visit -3. Administration of study treatment during visits 0
and 4b.
Study burden and risks
No side effects attributable to application of stem cells have been reported in
any patients so far. As this is a new treatment, the potential long term
effects of this cell therapy are unknown. There are potential complications
that may occur during surgery and on the days immediately following surgery
(such as bleeding, occurrence of perianal abscesses or wound infection).
During this study your blood will be drawn to perform a variety of tests. The
risk of drawing blood includes temporary discomfort, bruising, swelling and
redness in the area where the blood is taken.
No significant risks have been reported for magnetic resonance imaging because
it uses no radiation (unlike X rays). Some cases of mild dizziness have been
reported in people experiencing a certain feeling of claustrophobia in the room
where the scan is performed. However, this is uncommon and the test usually
takes approximately 30 minutes.
Calle Marconi 1
28760 - Tres Cantos - Madrid
Spanje
Calle Marconi 1
28760 - Tres Cantos - Madrid
Spanje
Listed location countries
Age
Inclusion criteria
1. Signed informed consent.
2. Patients with CD diagnosed at least 12 months earlier in accordance with accepted clinical, endoscopic, anatomical/topographical and/or radiologic criteria. France and Italy only: Patients with CD diagnosed at least 12 months earlier in accordance with accepted clinical, endoscopic, anatomical/topographical and/or radiological criteria, unresponsive (treatment failure and/or intolerance and/or contraindication) to conventional treatment, including anti-TNF.
3. Presence of complex perianal fistula with up to 3 external openings, assessed by MRI. The blinded fistulae branches visible though MRI are not considered fistula tracts but branches of the main tract. A complex perianal fistula is defined as a fistula that meets one or more of the following criteria:
- High fistulas (high inter-sphincteric, high trans-sphincteric, extra-sphincteric or supra sphincteric)
- Presence of 3 or fewer external openings associated to a complex perianal fistula.
4. Non-active or mildly active luminal CD defined by a CDAI <=220.
5. Patients of either sex aged 18 years or older. Good general state of health according to clinical history and a physical examination.
6. Women of a childbearing age with negative serum or urine pregnancy test (sensitive to 25 IU hCG). Both men and women should use appropriate birth control methods defined by the investigator.
Exclusion criteria
1. Presence of severe proctitis (prominent friability, spontaneous bleeding, multiple erosions, deep ulcers) or dominant active Crohns disease requiring immediate therapy, assessed by rectosigmoidoscopy
2. CDAI >220.
3. Presence of an abscess or collections >2 cm, unless a complete surgical debridement of the area has been performed, including drainage of the collection(s) and an MRI scan confirms absence of (residual) abscess before randomization.
4. Presence of setons. If present at screening they should be removed prior to treatment administration.
5. Presence of >3 external openings.
6. Rectal and/or anal stenosis.
7. Treatment with infliximab or any other anti-TNF agent in the 8 weeks before the cell treatment administration.
8. Patients having received adalimumab in the 4 weeks before the cell treatment adminsitration.
9. Treatment with tracrolimus or cyclosporine in the 4 weeks before the cell treatment administration.
10. HIV, HBV, HCV or treponema infection.
11. Persistent chronic bacterial infections of temporary nature as well as local infections unless succesfully treated prior liposuction, such as syphilis, brucellosis, typhus, melioidosis, q-fever, meningitis, or other.
12. Renal impairment defined by creatinine clearance below 60 ml/min calculated using Cockcroft-Gault formula (see appendix I) or the following laboratory ranges:
Total bilirubin > 1.5 x upper limit of normal (ULN)
AST and ALT > 2.5 X ULN
Serum creatinine > 1.5 ULN
13. Known history of abuse of alcohol or other addictive substances in the 6 months prior to inclusion.
14. Malignant tumor or patients with a prior history of malignant tumors.
15. Current or recent history of abnormal, severe, progressive, uncontrolled liver function, anemia, hepatic, hematological, gastrointestinal (except CD), endocrine, pulmonary, cardiac, neurological, psychiatric ,or cerebral disease.
16. Congenital or acquired immunodeficiencies.
17. Known allergies or hypersensivity to antibiotics including but not limited to penicillin, streptomycin, gentamicin, aminoglycosides; HSA; DMEM; materials of bovin origin; local anesthetics or gadolinium (MRI contrast).
18. Contraindication to MRI scan, (e.g., due to the presence of pacemakers, hip replacements or severe claustrophobia).
19. Liposuction with extraction of at least 100 cm3 of fat from the abdominal wall is technically unfeasible or the patient does not consent to the procedure.
20. Major surgery or severe trauma within the previous 6 months.
21. Pregnant or breastfeeding women.
22. Patients who do not wish to or cannot comply with study procedures.
23. Patients currently receiving, or having received within 3 months prior to enrolment into this clinical study, any investigational drug.
24. Patients unlikely to comply with 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 | EUCTR2008-004286-25-NL |
| CCMO | NL24602.000.08 |