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| ID | Type | Description | Link |
|---|---|---|---|
| 2024-512164-63-00 | EU Trial (CTIS) Number | ||
| 2024-512164-63-00 | Other Identifier | UE Trial (CTIS) Number |
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| Name | Class |
|---|---|
| Janssen-Cilag Ltd. | INDUSTRY |
| INSERM U1111 | UNKNOWN |
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Toxic Epidermal Necrolysis (TEN) are rare diseases that are dermatologic emergencies characterized by widespread epidermal necrosis and sloughing of skin. A hundred patients are affected each year in France. The main symptom is bullous and skin detachment > 10% which gradually progresses to extensive necrosis of the 100% BSA epidermis. The mortality rate is around 15-20% due to visceral inflammatory injuries and serious bacterial infections. The morbidity is also very important (92% at 1 year), especially ophthalmologic with high risk of blindness. There is currently no effective treatment.
Our team recently demonstrated that the severity of the disease correlates with the quantity and quality of CD8+ T lymphocytes which are activated in the active phase of disease. An activation marker has been identified, the CD38 receptor, which is very strongly expressed on the T clones responsible for the disease in the skin or blood of patients The CD38 receptor is the target of several commercial therapeutic antibodies, including DARATUMUMAB, which is currently used for the treatment of myeloma. DARATUMUMAB is a depleting antibody that eliminates cells strongly expressing this receptor.
The hypothesis is that a single intravenous infusion of DARATUMUMAB upon hospital admission of a patient with drug-induced NET would eliminate pathogenic T cells, thereby slowing disease progression, severity (% BSA with skin detachment, mortality rate) and sequelae.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental | Experimental | Single intravenous infusion of DARATUMUMAB 16 mg/kg body weight. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| DARATUMUMAB (DARZALEX®) | Drug | A single injection of DARZALEX 16 mg/kg body weight administered by intravenous infusion (day 1) in addition to standard symptomatic treatment of NET until re-epidermalization. |
| Measure | Description | Time Frame |
|---|---|---|
| From baseline up to 24 hours after end of infusion: tolerance criteria defined as occurence of infusion related reactions, Cytokine release syndrome, main hemostasis parameters or variation in main biological parameters (blood ionogram). | Tolerance criteria according to NCI-CTCAE v5 criteria is defined as occurence of infusion related reactions; Cytokine release syndrome is characterized by increased levels of serum pro-inflammatory mediators; Main hemostasis parameters (prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FBG), thromobin time (TT), and D-dimer (DD); Variation in main biological parameters (blood ionogram). | At baseline and 24 hours after completion of the infusion of DARZALEX. If a clinical symptom or reaction is observed during infusion, an additional blood samples will be taken after a single intravenous infusion of DARZALEX 16 mg/kg body weight at day 1. |
| Efficacy defined as stop of disease progression at Day 6 | The cessation of disease progression at day 6 (D6) will be assessed by evaluating the change in the percentage of body surface area with skin detachment (detached and/or bullous surfaces, and/or associated with Nikolsky's sign) between the baseline (before daratumumab administration) and day 6 (D6), according to the following rules :
| Day 6 after an intravenous injection of darzalex (16mg/kg) |
| The occurrence of grade 3 or higher cardiovascular, renal, thyroid, or intestinal adverse events within two months of injection (seven times the nine-day half-life of daratumumab) | Occurrence of grade >=3 cardiovascular, renal, thyroid or intestinal adverse events, according to NCI-CTCAE v5 criteria. | Up to 2 months after the DARATUMUMAB infusion. |
| Measure | Description | Time Frame |
|---|---|---|
| Measure time between index date (onset of first symptom) and initiation of DARATUMUMAB treatment (Day 1) | Total number of days between the unique intravenous infusion of DARATUMUMAB at day 1 and onset of first symptoms leading to the diagnosis of TEN (Toxic Epidermal Necrolysis) | From date of onset of first symptoms leading to the diagnosis of TEN (Toxic Epidermal Necrolysis) until the unique infusion of DARATUMUMAB treatment at (Day 1)] |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Benoit BENSAID, Hospital practitioner | Contact | +33 4 72 11 72 11 | benoit.ben-said@chu-lyon.fr | |
| Annie IUNG, Project Manager | Contact | +33 4 72 40 68 24 | annie.iung@chu-lyon.fr |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Reference Center for Toxic, Toxin and Toxidermal Bullous Dermatoses - E. Herriot Hospital | Lyon | 69437 | France |
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| ID | Term |
|---|---|
| D013262 | Stevens-Johnson Syndrome |
| ID | Term |
|---|---|
| D013280 | Stomatitis |
| D009059 | Mouth Diseases |
| D009057 | Stomatognathic Diseases |
| D003875 | Drug Eruptions |
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| ID | Term |
|---|---|
| C556306 | daratumumab |
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This is a prospective, single-center, open-label phase I/II study using an optimal two-stage SIMON-type design for efficacy/tolerance evaluation (Simon, 1989), with an additional stage for tolerance evaluation alone... :
The 2-month follow-up period is sufficient for the collection of clinico-biological criteria of interest.
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| Stop TEN progression delay: Time in days from start of DARATUMUMAB injection (Day 1) to cessation of progression | Total number of days between intravenous infusion of DARATUMUMAB (day 1) and the documented stopping progression of TEN | From the date of DARATUMUMAB infusion (Day 1) until the documented date of stopping progression of TEN, assessed up to 12 months or date of death from any cause |
| Complete re-epidermalization delay: Time in days from start of DARATUMUMAB infusion (Day 1) to complete re-epidermalization | The complete re-epidermalization is defined as disappearance of skin erosions AND return to normal skin. The complete re-epidermalization is the total number of days between DARATUMUMAB injection (day 1) to complete re-epidermalization. | From the date of DARATUMUMAB infusion (day 1) until the documented date of complete re-epidermization, assessed up to 12 months or date of death from any cause. |
| Hospital stay : measure the length of stay in one of the intensive care, burn, or internal medicine departments at Hôpital Édouard Herriot. | Length of stay in E. Herriot hospital units care: Time between admission and discharge from E Herriot hospital | From admission to end of 12-month follow-up period |
| Co-morbidities associated with the NET: document ophthalmological, gynecological, pulmonary, digestive, psychiatric, urological, stomatological/ORL, dermatological, hepatic, nephrological sequelae at 2, 6 and 12 months after Day1 (injection of Darzalex). | Absence or presence of any co-morbitity: ophthalmological, gynecological, pulmonary, digestive, psychiatric, urological, stomatological/ORL, dermatological, hepatic and nephrological adverse event related to the disease and grade according to NCI-CTCAE v5 criteria. | At 2 months, 6 months and 12 months after Day 1 (injection of Daratumumab) |
| Overall survival measure at Day 15 and 12 months after Darzalex infusion (D1) | Overall survival rate defined as percentage of deaths | At Day15 and 12 months after Darzalex infusion (Day 1). |
| D003872 |
| Dermatitis |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D004892 | Erythema Multiforme |
| D004890 | Erythema |
| D012872 | Skin Diseases, Vesiculobullous |
| D006968 | Hypersensitivity, Delayed |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D004342 | Drug Hypersensitivity |
| D064420 | Drug-Related Side Effects and Adverse Reactions |
| D064419 | Chemically-Induced Disorders |