| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| 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 | 10014989 |
| E.1.2 | Term | Epidermolysis bullosa |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 safety of INM-755 cream in patients with EB.
- To obtain preliminary evidence of efficacy of INM-755 cream on wound and non-wound
affected skin areas in patients with EB. |
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| E.2.2 | Secondary objectives of the trial |
| - To assess systemic exposure to cannabinol in a subset of patients. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Individuals must meet all of the following criteria to be included in the study:
1. Male or female patients aged ≥18 years with documented diagnosis of any of the following types of inherited EB:
• EB simplex
• Junctional EB
• Dystrophic EB
• Kindler EB
Enrolment will be extended to patients ≥12 years old and <18 years old after positive opinion of a DMC after their review of safety and tolerability data from at least 4 adult patients who have completed at least 2 weeks of study treatment.
2. Presence of at least 1 pair of index areas that are well matched in terms of type(s) of EB sign or symptom, severity, and size. To be eligible, the pair of index areas must be either non-wound areas with symptom of itch or wounds (that may or may not have associated pain or itch). Up to 2 pairs of index areas (1 pair of non-wound and 1 pair of wound index areas) can be selected and treated in each individual patient.
For non-wound itch index areas, both areas should meet the following criteria:
• Chronic itch, not associated with a wound, with a score ≥40 mm on a 100 mm VAS at the Screening Visit and with an average score ≥40 mm during the 7 days before the Baseline Visit, and present for the majority of time over the 6 weeks before to the Baseline Visit
• Absence of wounds at the Screening and Baseline Visits that could qualify as an index wound (see below) in the index areas or that require wound dressing.
• The area cannot also have a wound that has healed (re-epithelialised) within the past 3 weeks prior to Screening.
• Extension of each index area to be treated should not exceed 20% of BSA and should not be less than 1% of BSA
• A difference in the index areas to be treated not larger than 2-fold the area of the smallest index non-wound itch area at the Screening Visit
• Additional signs or symptoms of EB other than itch from selected index areas do not need to be matched.
If the pair of index areas are wounds, both wounds should meet all following characteristics:
• Wounds with a surface area ≥5 cm2 and ≤50 cm2 inclusive at the Screening and Baseline Visits and aged ≥3 weeks at the Screening Visit
• At Baseline Visit, each index wound should not present a surface reduction ≥30% from the Screening Visit
• To be considered well-matched the index wounds must have:
a. a difference in the surface area not larger than 2-fold the surface of the smallest index wound at the Screening Visit
b. both must fit into the same duration window of either ≥3 weeks to 3 months before the Screening Visit or >3 months
c. not located at anatomical sites with high likelihood of accidental trauma (e.g., knees, elbows)
3. Female patients of childbearing potential or men whose sexual partners are women of childbearing potential (WOCBP) must be able and willing to use at least 1 method of contraception until the patient’s last study visit. The following are permitted contraceptive methods: intrauterine device, hormonal contraceptives (e.g., oral, patch, or injectable), male vasectomy (if vasectomy was medically confirmed). Abstinence from heterosexual intercourse is acceptable when this is the usual lifestyle of the patient. A female patient is considered not of childbearing potential when postmenopausal (at least 12 consecutive months without menses without an alternative medical cause) or otherwise permanently sterile (for which acceptable methods include hysterectomy, bilateral salpingectomy, or bilateral oophorectomy with or without hysterectomy).
4. If the patient is a female of childbearing potential, patient should have a negative urine pregnancy test result at Screening and Baseline Visits.
5. Must be willing to provide written consent (or assent from the patient and written informed consent from the parent or guardian for patients aged <18 years) and to comply with the requirements of the study protocol. |
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| E.4 | Principal exclusion criteria |
Individuals meeting any of the following criteria at Screening or Baseline are ineligible to participate in this study:
1. EB index areas have evidence of infection.
2. Patient has evidence of a systemic infection or has used systemic antibiotics for EB-related infections within 7 days before the Baseline Visit.
3. Administration of systemic corticosteroids within 30 days or of topical (except ophthalmic) corticosteroids on chosen index areas within 14 days before the Baseline Visit. Corticosteroids for inhalation or intranasal use are permitted provided they are taken at a stable dosing.
4. Immunosuppressive therapy or cytotoxic chemotherapy within 60 days before the Baseline Visit.
5. Use of any high potency opioid within 30 days prior to Baseline Visit.
6. Use of cannabis, cannabis extracts, or any cannabinoid products for medical or recreational use by any route of administration within 2 weeks prior to the Baseline Visit. The patient can be using the cannabinoid-containing product at Screening but must commit to avoiding cannabinoid use in the prescribed timeframe.
7. Patient has undergone stem cell transplant or gene therapy for the treatment of inherited EB.
8. History of malignancy including basal cell carcinomas and squamous cell carcinomas.
9. Arterial or venous disorder resulting in ulcerated wounds.
10. Uncontrolled diabetes mellitus.
11. Presence of chronic pruritus believed to be primarily attributable to concomitant pathologies or conditions other than EB (e.g., renal or cholestatic pathologies).
12. Patient has received blood transfusion to treat anaemia within the past 3 months.
13. Patient has received any investigational drug within 30 days or 5 half-lives (whichever is longer) before the Baseline Visit.
14. Patient has an underlying condition which in the opinion of the investigator places the patient at unacceptable risk.
15. Women who are pregnant, breastfeeding (lactating), or planning to become pregnant during the study.
16. Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary safety endpoints are:
• Incidence of treated index areas with erythema, oedema, scaling, and stinging/burning identified from local tolerability assessment (LTA) by
type of treatment and severity
• Treatment-emergent local adverse event (AE) incidence, severity, and relationship with treatment |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Other safety endpoints are:
• Treatment-emergent systemic AE incidence, severity, and relationship with treatment
• Change from Baseline (CFB) in vital signs
• Incidence of treatment-emergent abnormal physical examination findings
Efficacy Endpoints
Preliminary evidence of efficacy will be evaluated based on the following endpoints as applicable:
Non-wound Itch:
• CFB in weekly average non-wound itch severity summarised from daily assessments by the patient using a 100 mm visual analogue scale (VAS)
• Proportion of non-wound itch index areas achieving a 20 mm, 30 mm, or >30 mm reduction of itch VAS from Baseline to End of Treatment (EOT)
• Patient's Impression of Change of Non-wound Itch (PIC-I) as assessed by the Dynamic Pruritus Scale (DPS) at each index area after 2 weeks and 4
weeks of treatment
Wound Surface Area:
• Absolute and percent CFB in surface area of each index wound at the scheduled visits
• Incidence of at least 25%, 50%, 75%, and 100% reduction in surface area from Baseline and incidence of first complete closure (defined as
complete re-epithelialisation without drainage) of each index wound at the scheduled visits
• Time to achieve 50% reduction from Baseline in surface area of each index wound
• Time to achieve complete closure of each index wound
Procedural Wound Pain:
• CFB in weekly average index wound pain score associated with dressing change (procedural pain) summarised from assessments by the patient
using a 100 mm VAS
• Proportion of index wounds with associated procedural pain achieving a 20 mm, 30 mm, or >30 mm reduction of pain VAS from Baseline to EOT
• Patient’s Impression of Change-Procedural Pain (PIC-PP) for each wound index area after 2 weeks and 4 weeks of treatment
Background Wound Pain:
• CFB in weekly average index wound pain score not associated with dressing change (background pain) summarised from daily assessments by
the patient using a 100 mm VAS
• Proportion of index wounds with background pain achieving a 20 mm, 30 mm, or >30 mm reduction of pain severity from Baseline to EOT
• Patient’s Impression of Change-Background Pain (PIC-BP) for each wound index area after 2 weeks and 4 weeks of treatment
Wound Itch:
• CFB in weekly average wound itch summarised from daily assessments by the patient using a 100 mm VAS
• Proportion of index wounds with associated itch achieving a 20 mm, 30 mm, or >30 mm reduction of itch severity from Baseline to EOT
• Patient’s Impression of Change-Wound Itch (PIC-WI) for each index area after 2 weeks and 4 weeks of treatment
Pharmacokinetic Endpoint
The pharmacokinetic (PK) endpoint of this study is systemic exposure to cannabinol (CBN) measured at completion of treatment (in a subset of patients). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Intra individual comparison |
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| 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
| 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 | 9 |
| 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 |
| Serbia |
| Austria |
| France |
| Germany |
| Greece |
| Italy |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 0 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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