Evaluating the Therapeutic Efficacy of Filgrastim in Severe Bullous Drug Eruptions (Lyell and Stevens-Johnson Syndromes)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 42
- 试验地点
- 3
- 主要终点
- Arrest of the SJS/NET progression at day 5
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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)
干预措施: Filgrastim (Drug)
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)
干预措施: Placebo (Drug)
结局指标
主要结局
Arrest of the SJS/NET progression at day 5
时间窗: On day 5 (after 5 injections of ZARZIO or PLACEBO - D0: initiation of treatment)
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.
次要结局
- 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)
- Duration of hospitalization(15 days (maximal of SJS/NET episode's hospitalization))
- Adverse events(Until 1 year)
- Use of systemic corticosteroid therapy(Between day 0 and day 15)
- Evaluation of sequels(At day 45, day 60, day 90, day 180 and 1 year)
- Quality of life evolution(At day 60, day 180 and 1 year)
- Overall survival(Until 1 year)
- Premature discontinuation of experimental treatment(Between day 0 and day 5)
- Risk of developing Post Traumatic Stress Disorder (PTSD)(At day 0, day 7 and day 15)