Clinical trial NCT04651439: Severe Bullous Drug Eruption and Filgrastim
Official title: Evaluating the Therapeutic Efficacy of Filgrastim in Severe Bullous Drug Eruptions (Lyell and Stevens-Johnson Syndromes)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
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)
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2020-12-03
Enrollment: 42
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Arrest of the SJS/NET progression at day 5
timeFrame: On day 5 (after 5 injections of ZARZIO or PLACEBO - D0: initiation of treatment)
Secondary outcomes:
measure: Arrest of the SJS/NET progression
timeFrame: At day 3, day 7 and day 15
measure: Complete re-epidermization
timeFrame: At day 3, day 5, day 7, day 15 and day 45
measure: Overall survival
timeFrame: Until 30 days
measure: Overall survival
timeFrame: Until 1 year
measure: Duration of hospitalization
timeFrame: 15 days (maximal of SJS/NET episode's hospitalization)
measure: Premature discontinuation of experimental treatment
timeFrame: Between day 0 and day 5
measure: Adverse events
timeFrame: Until 1 year
measure: Use of systemic corticosteroid therapy
timeFrame: Between day 0 and day 15
measure: Evaluation of sequels
timeFrame: At day 45, day 60, day 90, day 180 and 1 year
measure: Quality of life evolution
timeFrame: At day 60, day 180 and 1 year
measure: Risk of developing Post Traumatic Stress Disorder (PTSD)
timeFrame: At day 0, day 7 and day 15
Other outcomes:
Locations:
city: LYON cedex 03
country: France
facility: Département d'Anesthésie-Réanimation , Hôpital Edouard Herriot, Hospices Civils de Lyon
city: Lyon
country: France
facility: Reference center for toxic bullous dermatoses and severe drug eruptions, Edouard Herriot Hospital, Hospices Civils de Lyon
city: Lyon
country: France
facility: Service de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon
Study officials:
References: