Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn's Disease

Crohn's Disease Clinical Trial

— ADMIRE-CD  

Official title:

A Phase III, Randomized, Double Blind, Parallel Group, Placebo Controlled, Multicentre Study to Assess Efficacy and Safety of Expanded Allogeneic Adipose-derived Stem Cells (eASCs) for the Treatment of Perianal Fistulising Crohn's Disease Over a Period of 24 Weeks and an Extended Follow-up Period up to 104 Weeks.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01541579
• Other study ID #: Cx601-0302
• Status: Completed
• Phase: Phase 3
• Start date: July 2012
• Est. completion date: November 2016

Study information

• Verified date: November 2019
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The current multicentre phase III study is proposed to confirm in an add-on therapy design compared to a placebo-control group, the efficacy of adipose-derived stem cells (eASCs) from healthy donors for the treatment of complex anal fistulas in patients with Crohn's disease over a 24-week period and an extended follow-up period up to 104 weeks.

Description:

The current multicentre phase III study is proposed to confirm in an add-on therapy design compared to a placebo-control group, the efficacy of adipose-derived stem cells (eASCs) from healthy donors for the treatment of complex anal fistulas in patients with Crohn's disease over a 24-week period and an extended follow-up period up to 104 weeks. Subject with perianal fistulising Crohn's disease will be treated with Cx601, suspension of eASCs, at a dose of 120 million cells administered by intralesional injection. The treatment of complex perianal fistulas by local application of eASCs intends to improve significantly the local conditions with very few inconveniences (ambulatory procedure) and minimal risk of possible complications (anal incontinence). Therefore, this is a new therapeutic resource that is expected to be safe and efficacious as well as is expected to improve the quality of life of the patients in this highly debilitating and chronic condition. This treatment would prevent one of the main causes of anal incontinence, would diminish recurrence of the fistula disease and would reduce drastically the significant disorders provoked by the standard fistula surgery in the patients. Indeed, patients can be discharged according to the "One Day Surgical" procedures (major ambulatory surgery).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 278
• Est. completion date: November 2016
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

The reference population will consist of patients with perianal fistulising Crohn´s disease refractory to at least one of the following treatments: antibiotics, immunosuppressants or anti-tumor necrosis factor (TNF). Naïve patients are excluded, and those patients refractory to antibiotics will represent less than 25% of the total recruited patients.

All of them must comply with the following inclusion criteria:

1. Signed informed consent.

2. Patients with Crohn's Disease (CD) diagnosed at least 6 months earlier in accordance with accepted clinical, endoscopic, histological and/or radiologic criteria.

3. Presence of complex perianal fistulas with a maximum of 2 fistulas (internal openings) and a maximum of 3 external openings, assessed by clinical assessment and MRI. Fistula must have been draining for at least 6 weeks prior to the inclusion. A complex perianal fistula is defined as a fistula that met one or more of the following criteria during its evolution:

• High inter-sphincteric, trans-sphincteric, extra-sphincteric or supra-sphincteric.

• Presence of = 2 external openings (tracts).

• Associated collections

4. Non-active or mildly active luminal CD defined by a CDAI = 220.

5. Patients of either sex aged 18 years or older

6. Good general state of health according to clinical history and a physical examination.

7. For women of a childbearing age, they must have negative serum or urine pregnancy test (sensitive to 25 IU human chorionic gonadotropin (hCG)). Both men and women should use appropriate birth control methods defined by the investigator.

Exclusion Criteria:

1. Presence of dominant luminal active Crohn's disease requiring immediate therapy.

2. CDAI >220.

3. Concomitant rectovaginal fistulas

4. Patient naïve to specific treatment for perianal fistulising Crohn's disease including antibiotics

5. Presence of an abscess or collections > 2 cm, unless resolved in the preparation procedure (week -3 to day 0).

6. Presence of > 2 fistular lesions.

7. Presence of > 3 external openings.

8. Rectal and/or anal stenosis and / or active proctitis, if this means a limitation for any surgical procedure.

9. Patient who underwent surgery for the fistula other than drainage or seton placement.

10. Patient with diverting stomas

11. Patient with ongoing steroid treatment or treated with steroids in the last 4 weeks

12. Renal impairment defined by creatinine clearance below 60 ml/min calculated using Cockcroft-Gault formula or by serum creatinine = 1.5 x upper limit of normality (ULN)

13. Hepatic impairment defined by both of the following laboratory ranges:

• Total bilirubin = 1.5 x ULN

• Aspartate aminotransferase (AST) and alanine aminotransferase(ALT) = 2.5 x ULN

14. Known history of abuse of alcohol or other addictive substances in the 6 months prior to inclusion.

15. Malignant tumour or patients with a prior history of any malignant tumour, including any type of fistula carcinoma.

16. Current or recent history of abnormal, severe, progressive, uncontrolled hepatic, haematological, gastrointestinal (except CD), endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral disease.

17. Congenital or acquired immunodeficiencies.

18. Known allergies or hypersensitivity to antibiotics including but not limited to penicillin, streptomycin, gentamicin, aminoglycosides; Human Serum Albumin (HSA); Dulbecco Modified Eagle's Medium (DMEM); materials of bovine origin; local anaesthetics or gadolinium (MRI contrast).

19. Contraindication to MRI scan, (e.g., due to the presence of pacemakers, hip replacements or severe claustrophobia).

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 previously treated with eASCs can not be enrol into this clinical study.

25. Subjects who need surgery in the perianal region for reasons other than fistulas at the time of inclusion in the study, or for whom such surgery is foreseen in this region in the 24 weeks after treatment administration.

26. Contraindication to the anaesthetic procedure.

Related Conditions & MeSH terms

• Crohn Disease
• Crohn's Disease

Intervention

Other:
• Cx601
120 million cells administered by intralesional injection.
• Saline solution
24 mL saline solution by intralesional injection

Locations

Country	Name	City	State
Austria	Univ.-Klinik Innsbruck	Innsbruck
Austria	Krankenhaus	St. Veit/Glan
Austria	Medizinische Universität	Wien
Belgium	Hospital Oost-Limburg	Genk
Belgium	Gent University Hospital	Gent
Belgium	Leuven University Hospital	Leuven
Belgium	Hospital Hartziekenhuis	Roeselare
France	CHU d'Amiens	Amiens
France	CHU de Bordeaux	Bordeaux
France	CHU de Caen	Caen
France	Hôpital Beaujon	Clichy
France	CHRU de Lille	Lille
France	CHU de Marseille	Marseille
France	CHU de Nice	Nice
France	Hôpital Saint-Louis	Paris
Germany	Charite	Berlin
Germany	Krakenhaus Walfriede	Berlin
Germany	Klinikum Braunscheweig	Braunschweig
Germany	Klinikum Frankfurt	Frankfurt/Main
Germany	Evangelisches Krankenhaus Kalk	Köln
Germany	Klinikum Lüneburg	Lüneburg
Israel	Rambam MC	Haifa
Israel	Sharee Zedek MC	Jerusalem
Israel	Rabin MC	Petah Tikva
Israel	Tel Aviv Sourasky MC	Tel Aviv
Israel	Sheba MC	Tel Hashomer
Italy	Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola Malpighi	Bologna
Italy	Azienda Ospedaliero-Universitaria Careggi	Firenze
Italy	Instituto Clinico Humanitas IRCCS	Milano
Italy	Seconda Università degli Studi di Napoli	Napoli
Italy	Azienda Ospedaliera di Padova	Padova
Italy	Azienda Ospedaliera San Camillo-Forlanini	Rome
Italy	Università Cattolica del Sacro Cuore	Rome
Netherlands	AMC	Amsterdam
Netherlands	VUMC	Amsterdam
Netherlands	Catharina Ziekenhuis	Eindhoven
Netherlands	UMCU	Utrecht
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Reina Sofia	Cordoba
Spain	Hospital Juan Ramon Jimenez	Huelva
Spain	Fundacion Jimenez Diaz	Madrid
Spain	Hospital 12 de Octubre	Madrid
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital La Princesa	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital de Manises	Manises	Valencia
Spain	Son Espases	Palma de Mallorca
Spain	Hospital de Montecelo	Pontevedra
Spain	Hospital Virgen del Rocio	Seville
Spain	Hospital de Sagunto	Valencia
Spain	Hospital Universitario La Fe	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
Tigenix S.A.U.

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Germany,  Israel,  Italy,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Combine remission of perianal fistulising Crohn's	Combined Remission of perianal fistulising Crohn's disease defined as the clinical assessment of closure of all treated external openings (EO) that were draining at baseline despite gentle finger compression at week 24, and absence of collections > 2 cm of the treated perianal fistulas confirmed by centrally blinded MRI assessment by week 24.	24 weeks
Secondary	Efficacy Assessment by week 24	Clinical Remission (CR) defined as closure of all treated EO that were draining at baseline despite gentle finger compression, as clinically assessed; Response defined as closure of at least 50% of all treated EO that were draining at baseline, as clinically assessed; Time to Clinical Remission (time from treatment start to 1st visit with closure of all treated EO as described above); Time to Response (time from treatment start to 1st visit with closure of at least 50% of all treated EO as described above); Relapse defined, in patients with CR at previous visit, as reopening of any of the treated EO with active drainage, or the development of a perianal collection > 2 cm of the treated perianal fistulas confirmed by centrally blinded MRI; Time to Relapse in patients with CR (time from CR to 1st visit with reopening of any of the treated EO as described above); Severity of the perianal CD, assessed with the PDAI; QoL assessed by IBDQ; CDAI score; Van Assche	24 weeks
Secondary	Efficacy Assessment by week 52	Combined Remission of perianal fistulising Crohn's disease at week 52 (as defined for week 24); Clinical Remission defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed at week 52; Response defined as closure of at least 50% of all treated external openings that were draining at baseline, as clinically assessed at week 52; Time to Combined Remission by week 52 (as defined for week 24); Time to Clinical Remission by week 52 (as defined for week 24); Time to Response by week 52 (as defined for week 24); Relapse by week 52 in patients with Combined Remission at week 24 (as defined for week 24); Time to Relapse by week 52 in patients with Combined Remission at week 24 (as defined for week 24); Severity of the perianal Crohn's disease up to week 52 assessed PDAI; QoL up to week 52 by the IBDQ; CDAI score up to week 52; Van Assche score up to week 52	52 weeks
Secondary	Efficacy Assessment by week 104	Clinical Remission of perianal fistulising Crohn's disease defined as the clinical assessment of closure of all treated external openings that were draining at baseline despite gentle finger compression at week 104; Relapse by week 104 in patients with Combined Remission at week 52, defined as reopening of any of the treated external openings with active drainage as clinically assessed; Time to Relapse by week 104 in patients with Combined Remission at week 52 (defined as time from Combined Remission to first visit with reopening of any of the treated external openings with active drainage as clinically assessed); Severity of the perianal Crohn's disease, assessed with the Perianal Disease Activity Index (PDAI) up to week 104; Quality of Life (QoL) assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) up to week 104; CDAI score up to week 104	104 Weeks
Secondary	Safety analysis throughout the study:	Adverse events including: Treatment emergent Adverse Events (TEAEs), TEAEs related to study treatment, Treatment emergent Serious Adverse Events (TESAEs), TESAEs related to study treatment, TEAEs leading to study withdrawal, adverse events related to surgical procedure(s) to provide study treatment, deaths Only SAEs will be reported during the 2nd follow-up period between week 52 and week 104.; Physical examination; Vital signs; Laboratory tests (biochemistry, haematology, urinalysis)	week 24, 52 and 104