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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Fistules périanales dans la maladie de Crohn |
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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 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).
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Évaluer la tolérance à long terme de l’administration répétée de darvadstrocel chez des patients présentant une MC et des fistules périanales complexes, grâce à l’évaluation des événements
indésirables (EI), des EIG, des événements indésirables d’intérêt particulier (EIIP) et des rapports de situation spéciale (RSS).
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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.
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Évaluer l’efficacité à long terme de l’administration répétée de darvadstrocel chez des patients présentant une MC et des fistules périanales complexes. |
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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 current complex, draining, perianal fistulas with controlled or mildly active CD (defined as patient reported outcomes measure derived from CDAI [PRO-2] score <14) who have already received treatment with darvadstrocel, and their physician has planned a repeat administration for the original tract or for a new fistula tract.
5. A male subject who is nonsterilized* and sexually active with a female partner of childbearing potential agrees to use barrier method of contraception (e.g. condom with or without spermicide)* from signing of informed consent and until 1 year after repeat administration.
6. 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.
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1. Selon l’avis de l’investigateur, le (la) patient(e) est capable de comprendre et de respecter les exigences du protocole.
2. Le (la) patient(e) signe et date un formulaire de consentement éclairé (FCE) écrit et toute autorisation requise relative à vie privée avant toute activité de l’étude.
3. Le (la) patient(e) est un homme ou une femme âgé(e) d’au moins 18 ans
4. Le (la) patient(e) présente actuellement des fistules périanales drainantes complexes et une MC contrôlée ou légèrement active (définie comme un score de mesure de résultats rapportés par le patient dérivé du score CDAI [PRO-2] <14), ayant déjà reçu un traitement par darvadstrocel, et pour lequel (laquelle) le médecin a programmé une administration répétée pour le trajet fistulaire original ou pour un nouveau trajet fistulaire.
5. Un patient non stérilisé et sexuellement actif dont la partenaire est une femme en âge de procréer accepte d’utiliser un moyen de contraception mécanique (« barrière ») (par exemple, préservatif avec ou sans spermicide) depuis la signature du formulaire de consentement éclairé et jusqu’à 1 an après l’administration répétée.
6. Une patiente en âge de procréer et sexuellement active dont le partenaire est un homme non stérilisé accepte d’utiliser un moyen de contraception efficace/hautement efficace depuis la signature du formulaire de consentement éclairé et jusqu’à 1 an après l’administration répétée.
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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.
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 or MRI contrast.
4. The subject is currently participating in other studies with darvadstrocel.
5. The subject is currently receiving or has received any other investigational medicinal product (IMP) within the last 3 months before signing the ICF.
6. 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.
7. If male, the subject intends to donate sperm during this study.
8. 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).
9. The subject has a contraindication to the anesthetic procedure.
10. The subject has severe rectal and/or anal stenosis that would make it impossible to follow the surgery procedure.
11. The subject has severe proctitis (rectal ulcers >0.5 cm) that would make it impossible to follow the surgery procedure.
12. The subject has any prior invasive malignancy diagnosed within the last 3 years before screening visit. Subjects with basal cell carcinoma of the skin completely resected outside the perineal region can be included.
13. The subject has a current or recent (within 6 months before the screening 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.
14. The subject has had major surgery of the gastrointestinal tract within 6 months before screening, including local perianal surgery, other than curettage/draining for the fistula, and/or treatment with darvadstrocel within 6 months before study entry. |
1. Le (la) patient(e) n’a pas eu de réponse clinique à un traitement antérieur par darvadstrocel, la réponse clinique étant définie comme la fermeture d’au moins 50 % de tous les orifices externes traités des fistules, qui étaient initialement drainants, malgré une compression digitale douce.
2. Le (la) patient(e) a des antécédents d’hypersensibilité ou d’allergies au darvadstrocel ou à des produits apparentés.
3. Le (la) patient(e) a des antécédents d’hypersensibilité ou d’allergies à la pénicilline ou aux aminoglycosides, au DMEM (Dulbecco modified eagle medium, milieu de Eagle modifié de Dubelcco), au sérum bovin, aux anesthésiques locaux ou au gadolinium ou à un produit de contraste pour IRM.
4. Le (la) patient(e) participe actuellement à d’autres études utilisant le darvadstrocel.
5. Le (la) patient(e) reçoit actuellement ou a reçu un autre médicament à l’étude (ME) au cours des 3 derniers mois avant la signature du FCE.
6. La patiente est enceinte ou allaite ou prévoit une grossesse avant la participation à la présente étude, pendant l’étude ou a l’intention de faire un don d’ovules pendant cette période.
7. Le patient prévoir de faire un don de sperme pendant cette étude.
8. Le (la) patient(e) présente une contre-indication à l’examen IRM (par exemple, en raison de la présence d’un stimulateur cardiaque, d’une prothèse de hanche, d’une claustrophobie sévère, ou d’une insuffisance rénale selon la définition des directives cliniques locales).
9. Le (la) patient(e) présente une contre-indication au protocole anesthésique.
10. Le (la) patient(e) présente une sténose rectale et/ou anale sévère rendant impossible la réalisation du protocole chirurgical.
11. Le (la) patient(e) présente une proctite sévère (ulcères rectaux > 0,5 cm) rendant impossible la réalisation du protocole chirurgical.
12. Le (la) patient(e) présente des antécédents de cancer invasif diagnostiqué dans les 3 dernières années précédant la visite de sélection Les patients ayant eu un carcinome basocellulaire cutané complètement réséqué, en dehors de la région périanale, peuvent être inclus.
13. Le (la) patient(e) présente actuellement ou a des antécédents récents (dans les 6 mois précédant la visite de sélection) d’une pathologie sévère progressive et/ou non contrôlée hépatique, hématologique, gastro-intestinale (autre que MC), rénale, endocrinienne, pulmonaire, cardiaque, neurologique ou psychiatrique pouvant augmenter le risque lié à la participation du patient à l’étude et/ou compromettre son observance des activités de l’étude
14. Le (la) patient(e) a eu une intervention chirurgicale majeure du tube digestif dans les 6 mois précédant la sélection, y compris une chirurgie périanale locale, autre qu’un curetage/drainage de fistule, et/ou un traitement par darvadstrocel dans les 6 mois précédant l’entrée dans l’étude.
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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
– Ectopic tissue formation
– Medication errors
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L’objectif principal de tolérance sera évalué d’après les critères d’évaluation suivants :
• Incidence des événements indésirables apparaissant sous traitement (EIAT).
• Incidence des événements indésirables graves apparaissant sous traitement (EIGAT).
• Incidence des RSS (grossesse)
• Incidence d’EIIP spécifiques :
o Immunogénicité/réactions allo-immunes
o Hypersensibilité
o Transmission d’agents infectieux
o Tumorigénicité
o Formation de tissu ectopique
o Erreurs médicamenteuses
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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.
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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 investigational medicinal product (IMP) administration.
> Combined remission of complex perianal fistula(s) is defined as the closure of all treated
external openings that were draining at baseline (ie, screening 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 24, 52, 104, and 156 after IMPadministration.
> 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 24, 52, 104, and 156 after IMP
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.
> Relapse is defined as reopening of any of the treated fistula(s) external openings that were
in clinical remission at Week 24, with active drainage as clinically assessed,
OR
> The development of a perianal fluid collection >2 cm (in at least 2 dimensions) confirmed
by centrally read MRI assessment.
- Time in days from Week 24 to reopening of any of the treated external openings with active drainage as clinically assessed OR the presence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistulas confirmed by centrally read MRI assessment.
- Proportion of subjects with new anal abscess in treated fistula.
- Change from baseline to Weeks 6, 24, 52, 104, and 156 after IMP administration in scores of discharge and pain items of Perianal Disease Activity Index (PDAI) score.
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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. |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
To assess the effect of darvadstrocel on microbiome diversity (optional). |
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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 | 5 |
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
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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 | 4 |
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 | 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 |