| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Perianal fistulising Crohn´s disease
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment for perianal fistulising Crohn´s disease |
|
| 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 |
|
| 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 assess the long-term safety of repeat administration of darvadstrocel in subjects with CD and complex perianal fistula by evaluation of AEs, serious adverse events (SAEs), adverse events of special interest (AESIs), and special situation reports (SSRs).
|
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the long-term efficacy of repeat administration of darvadstrocel in subjects with CD and complex perianal fistula.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
2. The subject signs and dates a written, informed consent form (ICF) and any required privacy authorization before the initiation of any study procedures.
3. The subject is male or female and aged 18 years or older.
4. The subject has complex perianal fistula(s) with a maximum of 2 internal openings and a maximum of 3 external openings based on clinical assessment and a reading of a locally performed contrast enhanced (gadolinium) pelvic MRI. Fistula(s) must have been draining for at least 6 weeks prior to baseline visit. A complex perianal fistula is defined as a fistula that meets 1 or more of the following criteria:
a) High inter-sphincteric, high trans-sphincteric, extra-sphincteric or suprasphincteric.
b) Presence of ≥2 external openings.
c) 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. The subject has already received treatment with darvadstrocel for a complex perianal fistula at least 6 months prior to baseline visit for retreatment, and their physician has planned a repeat treatment administration for the original tract (full remission not obtained or relapse of fistula draining) or for a new complex perianal fistula tract.
6. The subject has controlled or mildly active CD (defined as patient reported outcomes measure derived from Crohn’s Disease Activity Index [CDAI] patient reported outcome score-2 [PRO-2] score <14).
7. A male subject who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use barrier method of contraception (eg, condom with or without spermicide) from signing of informed consent and until 1 year after repeat administration.
8. A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to use a highly effective/effective method of contraception from signing of informed consent and until 1 year after repeat administration. |
|
| E.4 | Principal exclusion criteria |
1. The subject has lack of clinical response to prior treatment with darvadstrocel, where clinical response is defined as closure of at least 50% of all treated external fistula openings that were draining at baseline despite gentle finger compression or in the case of a unique fistula, a partial closure of the fistula.
2. The subject has a history of hypersensitivity or allergies to darvadstrocel or related compounds.
3. The subject has a history of hypersensitivity or allergies to penicillin or aminoglycosides; Dulbecco modified eagle medium; bovine serum; local anesthetics or gadolinium.
4. The subject is currently participating in a double-blind clinical study with darvadstrocel. Subjects participating in the ongoing INSPIRE registry (Alofisel-5003) study would need to withdraw from that study in order to enroll in this study.
5. The subject is currently receiving or has received any other IMP within the last 3 months or at least 5 times the respective elimination half-life time, whichever is longer, before signing the ICF.
6. The subject has known or suspected COVID-19 by the investigator within the past 2 months (additional testing may be performed at the discretion of the investigator). Positive antibody
testing for COVID without other evidence of current or recent active infection does not exclude participation.
a) Subjects who were in screening at the time that COVID-19–related factors resulted in discontinuation may also be rescreened with approval of the sponsor or designee.
7. The subject has major alterations in any of the following laboratory tests:
a) Serum creatinine levels >1.5 times the upper limit of normal(ULN).
b) Total bilirubin >1.5 × ULN.
c) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3.0 × ULN.
d) Hemoglobin <10.0 g/dL.
e) Platelets <75.0 × 109/L.
f) Albumin <3.0 g/dL.
8. The subject has an increased risk for surgical procedure.
9. The subjects has a known chronically active hepatopathy of any origin, including cirrhosis and subjects with persistent positive hepatitis B surface antigen and quantitative hepatitis B virus polymerase chain reaction (PCR) or positive serology for hepatitis C virus (HCV) and quantitative HCV PCR within 6 months before the baseline visit.
10. If female, the subject is pregnant or breastfeeding, or intending to become pregnant before participating in this study, during the study, or intending to donate ova during such time period.
11. If male, the subject intends to donate sperm during this study.
12. The subject has a contraindication to MRI scan (eg, due to the presence of pacemaker, hip replacement, severe claustrophobia, or renal insufficiency as defined by local clinical guidelines).
13. The subject has a contraindication to the anesthetic procedure.
14. The subject has severe rectal and/or anal stenosis that would make it impossible to follow the surgery procedure.
15. The subject has severe proctitis (rectal ulcers >0.5 cm) that would make it impossible to follow the surgery procedure.
16. The subject has any prior invasive malignancy diagnosed within the last 3 years before baseline visit. Subjects with basal cell carcinoma of the skin completely resected outside the perineal region can be included.
17. The subject has a current or recent (within 6 months before the baseline visit) history of severe, progressive, and/or uncontrolled hepatic, hematologic, gastrointestinal (other than CD), renal, endocrine, pulmonary, cardiac, neurologic, or psychiatric disease that may result in subject’s increased risk from study participation and/or lack of compliance with study procedures.
18. The subject has had major surgery of the gastrointestinal tract within 6 months before baseline or any minor surgery of the gastrointestinal tract 3 months before baseline.
19. The subject has had local major perianal surgery and/or treatment with darvadstrocel within 6 months before baseline. The abscess drainage, cleaning surgery, or seton placement are not considered as "local major surgery" in this protocol.
20. The subject does not wish to or cannot comply with study procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of the study will include assessment of the following safety parameters:
- Incidence of treatment-emergent adverse events
- Incidence of treatment-emergent SAEs
- SSRs (pregnancy)
- Specific AESIs, including:
– Immunogenicity/alloimmune reactions
– Hypersensitivity
– Transmission of infectious agents
– Tumorgenicity, applying to malignant tumors only.
– Ectopic tissue formation
– Medication errors
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Subjects will be assessed before repeat administration at the baseline and preparatory visit, and at Weeks 6 (±8 days), 24 (±15 days), 52 (±15 days), 104 (±30 days), and 156 (±30 days) following repeat administration. The Week 6 assessment will be primarily to capture immunogenicity/donor-specific antibody (DSA)/soluble factors.
Blood samples for central laboratory tests will be collected at baseline, Weeks 24 (±15 days), 156 (±30 days), and the
early termination visit. Blood samples for DSA levels and exploratory immunogenicity testing will be collected at the
baseline visit and at Weeks 6 (±8 days), 24 (±15 days), and 156 (±30 days). Blood samples for these tests will be
analyzed in batches as the study progresses, and available results will be provided with the interim reports.
|
|
| E.5.2 | Secondary end point(s) |
Efficacy will be assessed by evaluating the following endpoints:
- Proportion of subjects who achieve combined remission of perianal fistula(s) at Weeks 24 and 156 after darvadstrocel administration, where combined remission is defined as:
- The closure of all treated external openings that were draining at baseline (ie, baseline visit), despite gentle finger compression,
AND
> Absence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by central MRI assessment.
- Proportion of subjects who achieve clinical remission at Weeks 6, 24, 52, 104, and 156 after darvadstrocel administration.
> Clinical remission is defined as closure of all treated external fistula openings that were draining at baseline despite gentle finger compression.
- Proportion of subjects who achieve clinical response at Weeks 6, 24, 52, 104, and 156 after darvadstrocel administration.
> Clinical response is defined as closure of at least 50% of all treated external fistula openings that were draining at baseline despite gentle finger compression.
- Proportion of subjects with relapse from Week 24 combined remission, where relapse is defined as:
- Reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed that were in combined remission at Week 24,
OR
- The development of a collection >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by centrally read MRI assessment.
- Time to reopening of any of the treated external openings with active drainage as clinically assessed, measured in days relative to Week 24.
- Proportion of subjects with new perianal abscess in treated fistula.
- Change from baseline to Weeks 6, 24, 52, 104, and 156 after darvadstrocel administration in scores of discharge and pain items of Perianal Disease Activity Index (PDAI) score.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Subjects will be assessed before repeat administration at the baseline and preparatory visit, and at Weeks 6 (±8 days),
24 (±15 days), 52 (±15 days), 104 (±30 days), and 156 (±30 days) following repeat administration. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| To assess the effect of darvadstrocel on microbiome diversity (optional). |
|
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
