New Therapeutic Target for Toxic Epidermal Necrolysis (TEN) Using Anti-CD38+ Monoclonal Antibodies.

Официальное название

New Therapeutic Approach to Toxic Epidermal Necrolysis (TEN) Using Anti-CD38+ Antibodies in the Active Phase of the Disease - Phase I/II Study to Assess the Tolerance and Efficacy of DARATUMUMAB.

Обзор

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.

Вмешательства

• Препарат DARATUMUMAB (DARZALEX®)
  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.

Первичные конечные точки

• 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). [Срок оценки: 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 [Срок оценки: 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) [Срок оценки: Up to 2 months after the DARATUMUMAB infusion.]

Вторичные конечные точки (6)

• Measure time between index date (onset of first symptom) and initiation of DARATUMUMAB treatment (Day 1) [Срок оценки: 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)]]
• Stop TEN progression delay: Time in days from start of DARATUMUMAB injection (Day 1) to cessation of progression [Срок оценки: 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 [Срок оценки: 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. [Срок оценки: 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). [Срок оценки: 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) [Срок оценки: At Day15 and 12 months after Darzalex infusion (Day 1).]

Критерии участия

Критерии включения

• Adult, over 18 years old, with drug-induced SJS/NET, proven or very strongly suspected (indirect argument of certainty) and confirmed by the evaluator.
• SJS or NET or overlap syndrome evolving for less than 7 days prior to inclusion and with a progression of the detachment or rash observed within 48 hours prior to DARATUMUMAB treatment.
• Negative hepatitis B screening (HBs, anti HBs and HBc).
• The patient (or a trusted support person, family member, or close relative in case of emergency) must be capable of understanding the objectives of the trial and must have given free, informed, and express consent.
• Patient affiliated to the Social Security system or benefiting from a similar system.
• Negative beta HCG pregnancy test for women of childbearing potential and agreement to use effective contraception during the study and up to 3 months after stopping DARATUMUMAB treatment.

Критерии исключения

• Patient with Lyell syndrome induced by immunotherapy.
• Known hypersensitivity to the active substance (DARZALEX) or to one of the excipients (L-histidine, L-histidine hydrochloride monohydrate, L-methionine, Polysorbate 20 Sorbitol -E420).
• Patient with known hereditary fructose intolerance (HFI).
• Patient with known history of chronic obstructive pulmonary disease (COPD).
• Patient admitted with septic shock.
• PMNs < 1,500 /mm3 on CBC at inclusion visit.
• Pregnant or breast-feeding women.
• Patient under protective measures (safeguard, curatorship, guardianship) or deprived of liberty.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

• Reference Center for Toxic, Toxin and Toxidermal Bullous Dermatoses - E. Herriot Hospital — Lyon

Идентификаторы

NCT: NCT07110662 · 69HCL23_1000 · 2024-512164-63-00 · 2024-512164-63-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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