| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Perianal fistulising Crohn´s disease |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment for perianal fistulising Crohn´s disease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002156 |
| E.1.2 | Term | Anal fistula |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the Combined Remission of complex perianal fistula(s), defined as the clinical assessment at Week 24 of closure of all treated external openings that were draining at baseline despite gentle finger compression, and absence of collections >2 cm (in at least 2 dimensions) confirmed by blinded central MRI assessment at Week 24. |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of Cx601 as compared to placebo in clinical remission at Week 24 and in time to clinical remission (weeks).
- To evaluate the efficacy and safety of Cx601 as compared to placebo in other clinical and time-to-event related endpoints at Weeks 24 and 52
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
(1) Signed informed consent
(2) Subjects of either gender ≥ 18 years and ≤75 years of age
(3) Subjects with CD diagnosed at least 6 months prior to Screening visit in accordance with accepted clinical, endoscopic, histological and/or radiological criteria
(4) Presence of complex perianal fistula(s) with a maximum of 2 internal openings and a maximum of 3 external openings based on assessment; a central reading of a locally performed contrast enhanced (gadolinium) pelvic MRI will be perfomed 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.
(5) Clinically controlled, non active or mildly active CD, during the last six months prior to Screening visit with:
1. a PRO-2 score < 14 at Screening, AND
2. 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: a 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 following must be documented, otherwise a new colonoscopy (as above) will be mandatory: the absence of ulcers larger than 0.5 cm in the colonic mucosa 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 > 2.0 g/dL or an unexplained rising C-reactive protein (CRP), > 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.
(6) Subjects 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
-TNFα antagonists
- Anti-integrin
- Anti-IL-12/23
(7) 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 (refraining from heterosexual intercourse), single-barrier method, vasectomy, adequate hormonal contraception (to have started at least 7 days prior to Screening visit), or an intra-uterine device (to have been in place for at least 2 months prior to Screening visit).
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| E.4 | Principal exclusion criteria |
(1) Concomitant rectovaginal or rectovesical fistula(s).
(2) Subject naïve to prior specific medical treatment for complex perianal fistula(s) including IS or anti-TNFs.
(3) 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 (week -3 to day 0).
(4) Severe rectal and/or anal stenosis and/or severe proctitis (defined as the presence of large [>0.5 cm] ulcers in the rectum) that make it impossible to follow the Surgery Procedure Manual.
(5) Subject with diverting stomas.
(6) Active, uncontrolled infection requiring parenteral antibiotics.
(7) Subject with ongoing systemic or rectal steroids for CD in the last 2 weeks prior to Preparation visit.
(8) Subjects with major alteration on any of the following laboratory tests or increased risk for the surgical procedure:
a. Serum creatinine levels >1.5 times the ULN
b. Total bilirubin >1.5 times the ULN (unless predominantly non-conjugated due to documented history of Gilbert’s syndrome)
c. AST/ALT >3.0 times the ULN
d. Hemoglobin <10.0 g/dL
e. Platelets <75.0 x 109/L
f. Albuminemia <3.0 g/dL
(9) Suspected or documented infectious enterocolitis within 2 weeks prior to Screening visit.
(10) 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.
(11) 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
(12) Subjects with primary sclerosing cholangitis
(13) Subjects 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.
(14) Congenital or acquired immunodeficiencies, including subjects known to be HIV carriers
(15) Known allergies or hypersensitivity to penicillin or aminoglycosides; DMEM; bovine serum; local anaesthetics or gadolinium (MRI contrast).
(16) Contraindication to MRI scan (e.g., due to the presence of pacemaker, hip replacement or severe claustrophobia).
(17) Severe trauma within 6 months prior to Screening visit.
(18) Pregnant or breastfeeding women.
(19) Subjects who do not wish to or cannot comply with study procedures.
(20) Subjects currently receiving, or having received any investigational drug within 3 months prior to Screening visit.
(21) Subjects previously treated with Cx601 or other allogeneic stem-cell therapy cannot be enrolled into this clinical study.
(22) 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.
(23) Subjects 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.
(24) Contraindication to the anaesthetic procedure.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of subjects who achieve combined remission at Week 24 after IMP administration, where combined remission is defined as:
- The closure of all treated external openings that were draining at baseline despite gentle finger compression
AND
- Absence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by blinded central MRI assessment.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Enpoints
- Proportion of subjects who achieve clinical remission at Week 24 after IMP administration, where clinical remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression.
- Time to clinical remission (weeks) assessed at Week 24, defined as the time from treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. Subjects who do not achieve clinical remission by Week 24 will be censored at that visit.
Other Secondary Efficacy Endpoints
- Proportion of subjects who achieve clinical response at Week 24 after IMP administration, where clinical response is defined as closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression.
- Time to clinical response (weeks) assessed at Week 24, defined as the time from treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline, despite gentle finger compression, as clinically assessed. Subjects who do not achieve clinical response by Week 24 will be censored at that visit.
- Proportion of subjects who achieve combined remission at Week 52 after IMP administration, where combined remission is defined as:
a) The closure of all treated external openings that were draining at baseline despite gentle finger compression,
AND
b) Absence of collection(s) >2 cm (in at least 2 dimensions) confirmed by blinded central MRI assessment.
- Proportion of subjects who achieve clinical remission at Week 52 after IMP administration, where clinical remission is defined as closure of all treated external openings that were draining at baseline despite gentle finger compression.
- Proportion of subjects who achieve clinical response at Week 52 after IMP administration, where clinical response is defined as closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression.
- Time to clinical remission (weeks) assessed at Week 52, defined as the time from treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. Subjects who do not achieve clinical remission by Week 52 will be censored at that visit.
- Time to clinical response (weeks) assessed at Week 52, defined as the time from treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. Subjects who do not achieve clinical response by Week 52 will be censored at that visit.
- Proportion of subjects with a relapse from Week 24 combined remission response, where a relapse is defined as:
a) Reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed in subjects who were in combined remission,
OR
b) The development of a perianal fluid collection >2 cm of the treated perianal fistulas confirmed by centrally read magnetic resonance imaging (MRI) assessment.
Safety Endpoints
- Incidence of treatment-emergent AEs (TEAEs)
- Incidence of treatment-emergent SAEs.
- Incidence of adverse events of special interest (AESIs).
- Vital signs.
- Laboratory parameters
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at 24 and 52 weeks after the treatment |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Hungary |
| Israel |
| Italy |
| Poland |
| Spain |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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