Clinical Trials

Inclusion Criteria:

• Signed informed consent.
• Patients of either gender ≥ 18 years and ≤ 75 years of age.
• Patients with Crohn’s Disease (CD) diagnosed at least 6 months prior to Screening visit in accordance with accepted clinical, endoscopic, histological and/or radiological criteria.
• Presence of complex perianal fistula(s) with a maximum of 2 internal openings and a maximum of 3 external openings based on clinical assessment; a central reading of locally performed contrast  enhanced (gadolinium) pelvic MRI will be performed to confirm location of the fistula and potential associated perianal abscess(es). Fistula(s) must have been draining for at least 6 weeks prior to Screening visit. Actively draining simple subcutaneous fistula(s), at the time of Screening visit, are not allowed in this study. A complex perianal fistula is defined as a fistula that meets one or more of the following criteria:
  • High inter-sphincteric, high trans-sphincteric, extra-sphincteric or supra-sphincteric
  • Presence of ≥ 2 external openings;
  • Associated perianal abscess(es).
    • Note: Abscesses that are larger than 2 cm in at least 2 dimensions on MRI must be confirmed to have been drained adequately by the surgeon during the preparation curettage in order to be eligible.
• Clinically controlled, non active or mildly active CD, during the last six months prior to Screening visit with:
  • A PRO-2 score < 14 at Screening; and
  • A colonoscopy documenting the absence of ulcers larger than 0.5 cm in the colonic mucosa:
  • If colonoscopy data are not available within 6 months prior to Screening:
    • Simple Endoscopic Score for CD (SES-CD) ≤ 6 with absence of rectal ulcers larger than 0.5 cm must be documented in a colonoscopy performed at Screening before randomization.
  • If colonoscopy data are available within 6 months prior to Screening:
    • The absence of ulcers larger than 0.5 cm in the colonic mucosa must be documented, otherwise a new colonoscopy at Screening before randomization, will be  mandatory; and
    • The improvement or no worsening in abdominal pain and/or in the diarrhea, sustained for one week or more, since the last colonoscopy was performed in the clinical records until Screening visit; and 
    • No hemoglobin decrease greater than 2.0 g/dL or an unexplained rising C-reactive protein (CRP), greater than 5.0 mg/L to a concentration above the referenced ULN (unless the rise is due to a known process other than luminal Crohn’s Disease), since the last colonoscopy was performed as compared to results during the Screening visit; and
    • No initiation or intensification of treatment with corticosteroids, immunosuppressants or mAbs dose regimen since the last endoscopy up to Screening visit.
• Patients whose perianal fistulas were previously treated and have shown an inadequate response (absence of closure of part or all fistula tracts, or new fistula during induction treatment) or a loss of response (fistula relapse during maintenance treatment after initial fistula closure) while they were receiving either an immunosuppressive agent or TNF-α antagonist or vedolizumab or ustekinumab, or having documented intolerance (occurrence, at any time, of an unacceptable level of treatment-related side effects that makes necessary treatment discontinuation) to any of these treatments administered at least at approved or recommended doses during the minimum period mentioned:
  • Immunosuppressive agents: at least 3 months treatment with azathioprine (2-3 mg/kg/day), 6-mercaptopurine (1-1.5 mg/kg/day), or subcutaneous/intramuscular methotrexate (25  mg/week) prior to Screening for the study.
  • TNFα antagonists:
    • Infliximab: at least 14 weeks treatment at the approved doses for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: 1  intravenous dose of 5 mg/kg followed by the same dose 2 and 6 weeks after. For maintenance: 5-10 mg/kg intravenously every 8 weeks, or more frequently;
    • Adalimumab: at least 14 weeks treatment at the approved doses for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: 1 subcutaneous dose of 160 mg, followed by 80 mg 2 weeks after. For maintenance: 40 mg subcutaneously every other week, or weekly;
    • Certolizumab pegol: at least 14 weeks treatment at the approved doses for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: 1 subcutaneous dose of 400 mg, followed by the same dose 2 and 4 weeks after. For maintenance: 400 mg subcutaneously every 2 to 4 weeks;
  • Anti-integrin: at least 14 weeks treatment of the approved dose for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: vedolizumab 300 mg. For maintenance:  vedolizumab 300 mg every 4 to 8 weeks.
  • Anti-IL-12/23: at least 16 weeks treatment of the approved dose in Crohn´s disease prior to screening for the study. For induction: ustekinumab[40], approximately 6 mg/kg intravenously initially then followed by 90 mg subcutaneously every 8 weeks.
• Women of childbearing potential (WCBP) must have negative serum pregnancy test at Screening (sensitive to 25 IU human chorionic gonadotropin [hCG]). Both WCBP or male patients participating in this study, with a WCBP as partner, must agree to use an adequate method of contraception during the entire duration of the study. An adequate method of contraception is defined as complete, non-periodic sexual abstinence, single barrier method, vasectomy, adequate hormonal contraception (to have started at least 7 days prior to Screening visit), or an intrauterine device (to have been in place for at least 2 months prior to Screening visit).
• A WCBP, for the purposes of this study, is a sexually mature female; who is not surgically sterile by means of a prior hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; and has not been naturally postmenopausal for at least the last 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Exclusion Criteria:

• Concomitant rectovaginal or rectovesical fistula(s).
• Patient naïve to prior specific medical treatment for complex perianal fistula(s) including IS or anti-TNFs.
• Presence of a perianal collection >2 cm in at least two dimensions on the central reading MRI at Screening visit that was not adequately drained as confirmed by the surgeon during the preparation procedure.
• Severe rectal and/or anal stenosis and/or severe proctitis (defined as the presence of large [>0.5 cm diameter] ulcers in the rectum) that make impossible to follow the Surgery Procedure Manual.
• Patient with diverting stomas.
• Active, uncontrolled infection requiring parenteral antibiotics.
• Patient with ongoing systemic or rectal steroids for CD in the last 2 weeks prior to the Preparation visit.
• Patients with major alteration on any of the following laboratory tests or increased risk for the surgical procedure:
  • Serum creatinine levels > 1.5 times the ULN;
  • Total bilirubin > 1.5 times the ULN (unless predominantly non-conjugated due to documented history of Gilbert’s syndrome);
  • AST/ALT > 3 times the ULN;
  • Hemoglobin < 10.0 g/dL;
  • Platelets < 75.0 x 10^9/L;
  • Albuminemia < 3.0 g/dL.
• Suspected or documented infectious enterocolitis within 2 weeks prior to Screening visit.
• Any prior invasive malignancy diagnosed within the last 5 years prior to Screening visit. Patients with basal-cell carcinoma of the skin completely resected outside the perineal region can be included.
• Current or recent (within 6 months prior to the Screening visit) history of severe, progressive, and/or uncontrolled hepatic, haematological, gastrointestinal (other than CD), renal, endocrine, pulmonary, cardiac, neurological or psychiatric disease that may result in patients increased risk from study participation and/or lack of compliance with study procedures.
• Patients with primary sclerosing cholangitis.
• Patients with known chronically active hepatopathy of any origin, including cirrhosis and patients with persistent positive HBV surface antigen (HBsAg) and quantitative HBV polymerase chain reaction (PCR), or positive serology for HCV and quantitative HCV PCR within 6 months prior to Screening visit.
• Congenital or acquired immunodeficiencies, including patients known to be HIV carriers.
• Known allergies or hypersensivity to penicillin or aminoglycosides; DMEM (Dulbecco Modified Eagle’s Medium); bovine serum; local anaesthetics or gadolinium (MRI contrast).
• Contraindication to MRI scan (e.g., due to the presence of pacemaker, hip replacement or severe claustrophobia).
• Severe trauma within 6 months prior to Screening visit.
• Pregnant or breastfeeding women.
• Patients who do not wish to or cannot comply with study procedures.
• Patients currently receiving, or having received any investigational drug within 3 months prior to Screening visit.
• Patients previously treated with Cx601 or other allogeneic stem-cell therapy cannot be enrolled into this clinical study.
• Any major surgery of the GI tract (including one or more segments of the colon or terminal ileum) within 6 months prior to screening or any minor surgery of the GI tract within 3 months prior to screening.
• Patients who had local perianal surgery other than drainage for the fistula within 6 months prior to the Screening visit, or those who may need surgery in the perianal region for reasons other than fistulas at the time of inclusion in the study.
• Contraindication to the anaesthetic procedure.