Severe Bullous Drug Eruption and Filgrastim

NCT ID: NCT04651439

Last Updated: 2024-05-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-13
• Study Completion Date: 2026-05-13

Brief Summary

Toxic epidermal necrolysis (TEN) including Stevens Johnson (SJS) and Lyell syndromes represent the most severe drug eruptions. It is an allergic disorder caused by cytotoxic T lymphocytes, specific of drugs, responsible for the destruction of keratinocytes by apoptosis. Regulatory T cell (CD25 high CD4+), normally responsible for controlling the activation of cytotoxic T lymphocytes, have altered function. Despite the progress made in the pathophysiological understanding of TEN, there is currently no effective treatment.

The main symptom is bullous and skin peeling > 10% giving the appearance of great burns. The death rate is estimated between 30 and 40% due to visceral inflammatory injuries and bacterial superinfection. The risk of mortality is estimated during the initial treatment by calculating the SCORTEN (mortality>10% if SCORTEN>2, mortality>90% if SCORTEN>5). The morbidity is also very important (92% at 1 year), especially ophthalmologic with high risk of blindness...

The therapeutic potential of G-CSF (Granulocyte-Colony Stimulating Factor) in TEN is supported by several observations.

The G-CSF promotes skin healing. This has been shown in human burns, with a significant reduction in healing time under G-CSF. The mechanisms associate the growth factor effect on keratinocytes, macrophages stimulation and metalloprotease activity allowing tissue remodeling limiting sequels onset. Otherwise, healing altered in deficient G-CSF mice is corrected by the growth factor injection.

The G-CSF is an immunomodulator whose activities appear to justify use in TEN :

• Polarization of immune response to Th2 non-cytotoxic (anti Th1),
• Preferential differentiation of naive LT (T lymphocytes) in regulator LT (CD25 high CD4+) and mobilization of regulator LT of the spinal cord to altered tissues.

The G-CSF was used in a few cases of TEN with great efficacy. No data is available concerning sequels of SJS/TEN in treated patients.

This clinical trial program, by providing proof of the efficacy of filgrastim in SJS/TEN, should allow progress in care of this serious toxics diseases. In the future, it could thus reduce the significant morbidity of these syndromes with a high rate of sequelae.

Conditions

Rare Diseases; Toxic Epidermal Necrolyses

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

FILGRASTIM

Standard symptomatic treatment of the SJS/NET (until the reepidermization of the patient) + ZARZIO@ (30 MU/0,5mL and/or 48 MU/0,5mL - solution of 20 ml diluted in GLUCOSE 5%) administrated by IV or subcutaneous route over a period of 5 consecutive days (1 injection per day during 30 minutes)

Group Type: EXPERIMENTAL

Filgrastim

Intervention Type: DRUG

Injection of ZARZIO 30 MU/0,5mL and/or ZARZIO 48 MU/0,5mL, over a period of 5 consecutive days (1 injection per day during 30 minutes - - day 1 : set up standard treatment). The filgrastim solution will be diluted in 20 mL of 5% Glucose. The dose of ZARZIO administrated depends of the patient's weight :

• 20 to < 30kg = 0,3 mL of ZARZIO 48 MU/0,5mL (subcutaneous route)
• 30 to < 60kg = 0,5 mL of ZARZIO 30 MU/0,5mL (by IV)
• 60 to < 90kg = 0,5 mL of ZARZIO 48 MU/0,5mL (by IV)
• 90 to < 120kg = 2x0,5 mL of ZARZIO 30 MU/0,5mL (by IV)
• 120 to 150kg = 0,5 mL of ZARZIO 30 MU/0,5mL + 0,5 mL of ZARZIO 48 MU/0,5mL (by IV)
• > 150kg = 2x0,5 mL of ZARZIO 48 MU/0,5mL (by IV)

PLACEBO

Standard symptomatic treatment of the SJS/NET (until the reepidermization of the patient) + 20 ml GLUCOSE 5% administrated by IV route over a period of 5 consecutive days (1 injection per day during 30 minutes)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Injection of 20 mL of Glucose 5% solution over a period of 5 consecutive days (1 injection per day during 30 minutes - day 1 : set up standard treatment). The dose given is equivalent to that used for filgrastim :

• 20 to < 30kg = placebo not available because the injection must be done subcutaneously so the blind cannot be respected.
• 30 to < 60kg = 20mL of Glucose 5% solution (by IV)
• 60 to < 90kg = 20mL of Glucose 5% solution (by IV)
• 90 to < 120kg = 20mL of Glucose 5% solution (by IV)
• 120 to 150kg = 20mL of Glucose 5% solution (by IV)
• > 150kg = 20mL of Glucose 5% solution (by IV)

Interventions

Filgrastim

Injection of ZARZIO 30 MU/0,5mL and/or ZARZIO 48 MU/0,5mL, over a period of 5 consecutive days (1 injection per day during 30 minutes - - day 1 : set up standard treatment). The filgrastim solution will be diluted in 20 mL of 5% Glucose. The dose of ZARZIO administrated depends of the patient's weight :

• 20 to < 30kg = 0,3 mL of ZARZIO 48 MU/0,5mL (subcutaneous route)
• 30 to < 60kg = 0,5 mL of ZARZIO 30 MU/0,5mL (by IV)
• 60 to < 90kg = 0,5 mL of ZARZIO 48 MU/0,5mL (by IV)
• 90 to < 120kg = 2x0,5 mL of ZARZIO 30 MU/0,5mL (by IV)
• 120 to 150kg = 0,5 mL of ZARZIO 30 MU/0,5mL + 0,5 mL of ZARZIO 48 MU/0,5mL (by IV)
• > 150kg = 2x0,5 mL of ZARZIO 48 MU/0,5mL (by IV)

Intervention Type: DRUG

Placebo

Injection of 20 mL of Glucose 5% solution over a period of 5 consecutive days (1 injection per day during 30 minutes - day 1 : set up standard treatment). The dose given is equivalent to that used for filgrastim :

• 20 to < 30kg = placebo not available because the injection must be done subcutaneously so the blind cannot be respected.
• 30 to < 60kg = 20mL of Glucose 5% solution (by IV)
• 60 to < 90kg = 20mL of Glucose 5% solution (by IV)
• 90 to < 120kg = 20mL of Glucose 5% solution (by IV)
• 120 to 150kg = 20mL of Glucose 5% solution (by IV)
• > 150kg = 20mL of Glucose 5% solution (by IV)

Intervention Type: DRUG

Other Intervention Names

ZARZIO; GLUCOSE 5%

Eligibility Criteria

Inclusion Criteria

• Patient aged of 6 years old or more, presenting SJS/TEN, drug or infectious origin proofed and very strongly suspected (indirect certainty argument), confirmed by evaluator.
• SJS or TEN evolving since less than 7 days with a progression of the detachment or the eruption observed dating less than 48 hours.
• Patient and/or have right able to understand the objectives of the trial and having given their written consent to participate (parents for minors, have right for patients in immediate life-saving emergency).
• Patient registered with a social security scheme or benefiting from a similar scheme.
• Pregnancy test beta HCG negative for women of childbearing age

Exclusion Criteria

• Patient weighing less than 20kg
• Chronic myeloid pathology such as myeloid leukemia or AML (acute myeloid leukemia)
• Thrombophilia or thrombotic pathology in progress
• PNN (polymorphonuclear neutrophils) > 50.000/mm3 on the CBC (Complete Blood Count) during the inclusion visit
• Administration of G-CSF or GM-CSF within 5 days of inclusion
• Patient who received cyclosporine, anti-TNFalpha or intravenous immunoglobulins or lithium in the month prior the inclusion
• Pregnant or breastfeeding woman
• Patient under protective measure (safeguard measure, curatorship, guardianship) or deprived of liberty
• Patient in exclusion period after participation at other interventional clinical trial
• Known hypersensitivity to the active substance (FILGRASTIM) or to the one of the excipients (glutamine acid, sorbitol E420, Polysorbate 80)
• Patient presenting a known glucose intolerance or hereditary fructose intolerance
• Patient with a traumatic brain injury less than 24 hours
• Patient admitted with septic shock

• Minimum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospices Civils de Lyon

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Département d'Anesthésie-Réanimation , Hôpital Edouard Herriot, Hospices Civils de Lyon

Lyon, , France

Site Status: RECRUITING

Reference center for toxic bullous dermatoses and severe drug eruptions, Edouard Herriot Hospital, Hospices Civils de Lyon

Lyon, , France

Site Status: RECRUITING

Service de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon

Lyon, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Benoit BEN SAID, MD

Role: CONTACT

benoit.ben-said@chu-lyon.fr

472 117 211 ext. +33

Laurent MAGAUD

Role: CONTACT

laurent.magaud@chu-lyon.fr

472 112 805 ext. +33

Facility Contacts

Anne-Claire LUKASZEWICZ, MD

Role: primary

Benoit BEN SAID, MD

Role: primary

benoit.ben-said@chu-lyon.fr

472 117 211 ext. +33

Solène POUTREL, MD

Role: primary

Other Identifiers

69HCL19_0375

Identifier Type: -

Identifier Source: org_study_id