| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complex Perianal Fistulas in Crohn’s Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Crohn's Disease is a condition that damages the bowel wall. Complex perianal fistulas have several abnormal connections and openings, or with passages that go deep inside the tissue near anus. |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068659 |
| E.1.2 | Term | Perianal fistula |
| E.1.2 | System Organ Class | 100000004856 |
|
| 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 efficacy of darvadstrocel in combined remission at Week 24 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate;
the efficacy of darvadstrocel in clinical remission at Week 24 and Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.
the efficacy of darvadstrocel in clinical response at Week 24 and Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.
the efficacy of darvadstrocel in time to clinical remission up to Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.
the efficacy of darvadstrocel in time to clinical response up to Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.
the efficacy of darvadstrocel on relapse by Week 52 in pediatric subjects with combined remission at Week 24.
the safety of darvadstrocel for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years over 52 weeks. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility is determined according to the following criteria prior to entry into the study:
1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
2. The subject, or when applicable, the subject’s legally acceptable representative, signs and dates a written, informed consent/pediatric assent form and any required privacy authorization before the initiation of any study procedures.
3. The subject is male or female aged 4 to <18 years at the time of informed consent/pediatric assent.
4. The subject has a CD diagnosis based on accepted clinical, endoscopic, histological and/or radiologic criteria at least 6 months before the screening visit.
5. The subject has complex perianal fistula refractory to at least one of the following treatments:
immunosuppressants or biologics (anti-TNFs, anti-integrin, anti-interleukin [IL] 12/23).
Fistula(s) refractory to therapy are defined in this study as follows:
Immunosuppressants: Inadequate response after 3 months, based on clinical assessment, or more treatment with azathioprine, 6-mercaptopurine or methotrexate.
Biologics: Inadequate response after 14 weeks (16 weeks for anti-IL 12/23), based on clinical assessment, or more standard treatment for induction and maintenance.
6. A complex perianal fistula(s) that meets one or more of the following criteria, modified from the American Gastroenterological Association (AGA) technical review:
High intersphincteric, transsphincteric, extrasphincteric, or suprasphincteric as assessed by MRI.
Presence of 2 or 3 external openings (tracts) as assessed by clinical examination.
Associated fluid (abscess) collections as determined by MRI.
This study requires that the subject has complex perianal fistulas with a maximum of 2 internal openings and a maximum of 3 external openings, based on clinical assessment. Darvadstrocel treatment is targeted for fistulas that connect between internal and external openings. A central reading of a locally performed pelvic MRI will be performed to confirm the location of the fistula and potential associated perianal abscess(es). Fistulas must have been draining for at least 6 weeks before the screening visit. Subjects with actively draining simple subcutaneous fistulas, at the time of the screening visit, are not allowed in this study.
7. The subject has inactive or mildly active luminal CD defined by meeting all of the following criteria:
a. Colonoscopy, flexible sigmoidoscopy or rectoscopy performed either at screening or within the 6 months before screening, demonstrating no rectal ulcers larger than 0.5 cm. A subject who has documented rectal ulcers larger than 0.5 cm within the 6 months before screening but has undergone subsequent treatment may be eligible if there are no rectal ulcers larger than 0.5 cm on a sigmoidoscopy or rectoscopy performed after treatment or at
the time of screening.
b. The improvement of, or no worsening in stool frequency, sustained for 1 week or more, in the interval between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion criteria 7(a) and the screening visit.
c. No initiation or intensification of treatment with corticosteroids, immunosuppressants, or monoclonal antibody dose regimen between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion criteria 7(a) and the screening visit.
8. 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 the time of signing of informed consent/pediatric assent throughout the duration of the study. The female partner of a male subject should also be advised to use a highly effective method of contraception.
9. A female subject of childbearing potential* who is sexually active with a nonsterilized male partner agrees to use a highly effective method of contraception* from the time of signing of informed consent/pediatric assent throughout the duration of the study.
*Definitions and highly effective methods of contraception are defined in Section 9.1.10 and reporting responsibilities are defined in Section 9.1.11. |
|
| E.4 | Principal exclusion criteria |
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has received any investigational compound within 12 weeks/84 days before screening.
2. The subject has received darvadstrocel/eASC in a previous clinical study or as a therapeutic agent.
3. The subject is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress.
4. The subject weighs <10 kg at screening.
5. The subject has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at screening.
6. The subject has a history of hypersensitivity or allergies to darvadstrocel or any of its excipients.
7. The subject takes or is required to take excluded medications listed in Table 7.a.
8. The subject has concomitant perianal fistula(s) with only internal or external opening(s).
9. The subject has concomitant internal fistula(s) such as ileo-vesical, rectovaginal or ileo-colonic fistula(s).
10. The subject has an abscess >2 cm, unless resolved in the preparation procedure.
11. The subject has rectal and/or anal stenosis, and/or active proctitis, which would restrict the surgical procedure.
12. The subject underwent surgery for the fistula other than drainage or seton placement.
13. The subject has diverting stomas.
14. The subject has ongoing systemic corticosteroid treatment or has been treated with systemic corticosteroids within 4 weeks before screening.
15. The subject requires new treatment with immunosuppressants/anti-TNF agents during the screening period.
16. 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.
-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.
17. The subject requires surgery in the perianal region for reasons other than fistulas at the time of screening or foreseen either during the study and/or during the 24 weeks after treatment administration.
18. The subject has a serum creatinine ≥2 × upper limit of normal (ULN).
19. The subject has hepatic impairment defined by both of the following laboratory ranges:
a) Total bilirubin ≥1.5 × ULN.
b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥2 × ULN.
20. The subject has known history of abuse of alcohol or other addictive substances in the 6 months before screening.
21. The subject has malignant tumor or a prior history of any malignant tumor, including any type of fistula carcinoma.
22. The subject has current or recent (within 3 months before the screening) history of abnormal, severe, progressive, uncontrolled hepatic, hematologic, gastrointestinal (except CD), endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral disease.
23. The subject has either congenital or acquired immunodeficiencies, including subjects known to be HIV carriers or subjects with, in the judgment of the investigator, are suspected to have monogenic inflammatory bowel disease.
24. The subject has a known clinically significant 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, or positive serology for hepatitis C virus (IgG) and quantitative hepatitis C virus polymerase chain reaction at the screening visit.
25. The subject has known allergies or hypersensitivity to antibiotics (including benzylpenicillin/streptomycin, gentamicin [used in the darvadstrocel manufacturing process]) human serum albumin; Dulbecco Modified Eagle’s Medium, material of bovine origin, or local anesthetics.
26. The subject has previously received a bone marrow transplant.
27. The subject has a contraindication to MRI scan or other planned study procedures.
28. The subject has a contraindication to the anesthetic procedure.
29. The subject had major surgery or severe trauma within 6 months before the screening visit.
30. A female subject who is pregnant or is lactating or intending to become pregnant before participating in this study or during the study; or intending to donate ova during such time period.
31. If male, the subject intends to donate sperm during the course of this study.
32. The subject does not wish to or cannot comply with study procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint-Efficacy endpoint
Proportion of subjects who achieve combined remission at Week 24, 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 abscess(es) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by central MRI assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints-
Efficacy at Week 24
1. Proportion of subjects who achieve clinical remission at Week 24, where clinical remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression.
2. Proportion of subjects with clinical response at Week 24, 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.
Efficacy at Week 52
1. Proportion of subjects who achieve clinical remission at Week 52, where clinical remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression.
2. Time to clinical remission (weeks) assessed at each clinic visit up to Week 52. This is defined as the time from treatment start to first visit at which clinical remission is observed before Week 52; where clinical remission is said to occur if a clinical assessment shows closure of all treated external openings that were draining at baseline despite gentle finger compression.
3. Proportion of subjects with clinical response at Week 52, 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.
4. Time to clinical response (weeks) assessed at each clinic visit up to Week 52. This is defined as the time from treatment start to first visit at which clinical response is observed before Week 52; where clinical response is said to occur if a clinical assessment shows closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression.
5. Proportion of subjects with relapse by Week 52, in subjects with combined remission at Week 24, where relapse is defined as reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed in subjects who were in combined remission at Week 24.
Safety Endpoints
1. Incidence of AEs.
2. Incidence of SAEs.
3. Incidence of adverse events of special interest (AESIs).
4. Vital signs.
5. Laboratory parameters (biochemistry, hematology, and urinalysis). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Israel |
| Japan |
| Italy |
| Poland |
| Spain |
|
| 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
|
| Last patient last visit (LPLV) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
Print
