Severe Bullous Drug Eruption and Filgrastim

NCT04651439 | Recruiting Phase 2 DMC

• 1 other identifier: 69HCL19_0375
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 3

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

Keywords

Toxic Epidermal Necrolysis (TEN); Stevens-Johnson syndrome (SJS); Lyell's syndrome; Ganulocyte-Colony Stimulating Factor (G-CSF); Filgrastim; Randomized controlled trial (RCT)

Outcome Measures

Primary Outcomes (1)

• Arrest of the SJS/NET progression at day 5

  Comparison between the 2 arms of the proportion of patients with arrest of progression of skin detachment defined by a peeled surface and/or bullous and/or associated at a NIKOLSKY sign determined according to the stable burn table - Evaluation done by the Outcomes Assessor and the adjudication committee.

  On day 5 (after 5 injections of ZARZIO or PLACEBO - D0: initiation of treatment)

Secondary Outcomes (11)

• Arrest of the SJS/NET progression

  At day 3, day 7 and day 15

• Complete re-epidermization

  At day 3, day 5, day 7, day 15 and day 45

• Overall survival

  Until 30 days

• Overall survival

  Until 1 year

• Duration of hospitalization

  15 days (maximal of SJS/NET episode's hospitalization)

Study Arms (2)

FILGRASTIM

EXPERIMENTAL

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)

Drug: Filgrastim

PLACEBO

PLACEBO COMPARATOR

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)

Drug: Placebo

Interventions

Filgrastim 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)

Also known as: ZARZIO

FILGRASTIM

Placebo 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)

Also known as: GLUCOSE 5%

PLACEBO

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Patient weighing less than 20kg
• Chronic myeloid pathology such as myeloid leukemia or AML (acute myeloid leukemia)
• Thrombophilia or thrombotic pathology in progress
• Pregnant or breastfeeding woman
• Patient under protective measure (safeguard measure, curatorship, guardianship) or deprived of liberty
• 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

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (3)

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

Lyon, 69437, France

RECRUITING

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

Lyon, 69437, France

RECRUITING

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

Lyon, 69437, France

RECRUITING

MeSH Terms

Conditions

Rare Diseases; Stevens-Johnson Syndrome

Interventions

Filgrastim

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Stomatitis; Mouth Diseases; Stomatognathic Diseases; Drug Eruptions; Dermatitis; Skin Diseases; Skin and Connective Tissue Diseases; Erythema Multiforme; Erythema; Skin Diseases, Vesiculobullous; Hypersensitivity, Delayed; Hypersensitivity; Immune System Diseases; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Central Study Contacts

Benoit BEN SAID, MD

CONTACT

472 117 211; benoit.ben-said@chu-lyon.fr

Laurent MAGAUD

CONTACT

472 112 805; laurent.magaud@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: This is a single blind patient trial. The outcomes assessor of the primary endpoint outcome, the adjudication committee and the statistician, will also be blinded to the allocated treatment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2020
• First Posted: December 3, 2020
• Study Start: May 13, 2022
• Primary Completion: May 18, 2025
• Study Completion (Estimated): May 13, 2026
• Last Updated: May 8, 2024

Record last verified: 2024-05

Locations

FR (3)