Comparison Between Corticosteroid and Topical Steroids in the DRESS

Study Overview
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Brief Summary
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Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and severe multiorgan adverse drug reaction occurring within 2 to 6-8 weeks after a new drug intake. DRESS syndrome is defined by the combination of clinical manifestations, cutaneous, visceral and biological disturbances. Its prognosis is directly linked to severity of visceral involvement, with a mortality evaluated above 10%. Considering curative treatment, there is no consensus. Until now, no controlled trial has been performed. Systemic steroids are mainly used in first intention, in particular for management of visceral involvements, whatever their severity. From clinical practice, topical steroids are often used and could be helpful in the therapeutic management of DRESS. We propose to evaluate systemic steroids versus very potent topical steroids in a multicentric randomized controlled trial including defined moderate DRESS, ie the non-inferiority of very potent topical steroids in terms of remission of visceral involvement at Day30 and the superiority of very potent topical steroids in terms of delay to remission of skin involvement.

Official Title
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DRESS - Setting of Corticosteroid Treatment.

Conditions
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Drug Rash With Eosinophilia and Systemic Symptoms

Intervention / Treatment
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* Drug: Prednisone
* Drug: Clobetasol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patient age ≥ 18 years signing informed consent form DRESS diagnosis with at least 4 criteria a, b, c, d Skin rash occurring at least 10 days and not more than two months after continuous drug intake (or within less than 10 days in case of rechallenge) Fever ≥ 38 ° at the time of examination or fever ≥ 38.5 ° peak in the last 72 hours (amendment 2 : ANSM + CPP : 08/04/14) at least one visceral compatible : lymphadenopathy on at least two different sites measuring at least 1 cm in diameter transaminases > 2 upper limit of normal (ULN) or alkaline phosphatise > 3 ULN lung involvement defined by hypoxemia (capillary oximetry ≤ 95%) and/or interstitial lung disease on chest radiography or scanner, in absence of other lung disease myocarditis, pericarditis (ECG clinical suspicion and confirmed by echocardiography) renal impairment defined as creatinine increase above the normal laboratory value associated with leucocyturia > 1000 / mm3 or proteinuria, a Na / K ratio >1 and Urine Cyto-bacteriology (EBCU) sterile in the absence of preexisting renal disease d) At least one of the following haematological abnormalities: eosinophilia ≥ 0.7 g/l or > 10 % absolute lymphocytosis ≥ 5*10^9 /l presence of atypical blood lymphocytes Patient with moderate DRESS : defined by at least one reached as follows : pulmonary: interstitial pneumonia with oxygen partial pressure in arterial blood (PaO2) 60-75 mmHg without dyspnoea at rest Hepatic: transaminases ≥ 4 ULN and < 15 ULN and/or PAL ≥5 ULN and V factor 50% (amendment 2 : ANSM + CPP : 08/04/14) renal : acute renal failure and organic sharp increase in the 48 hours preceding the inclusion of more of 26.4 micromol/l creatinine and / or increase of 1.5 times the normal creatinine value and / or decrease of oliguria of less than 0.5 ml/kg/h followed by a 6 hours cord: pancytopenia (7≤Hb≤10 gr/dl and/or 50<p<100 G/L, 0.5<PNN≤1.5G/l) AND absence of cardiac, neurological or gastrointestinal (gut, pancreas) threatening Drug withdrawal Patient with health insurance (or entitled beneficiary) Patient accepting the constraints of the test Exclusion Criteria: uncontrolled sepsis unability to discontinue the medication(s) due known hypersensitivity to systemic or topical corticosteroids hepatitis B or C known, (active HIV status known suppressed by amendment 5 : ANSM16/04/2015 and CPP 07/04/2015) (Patient already treated by corticosteroid : More than 48 hours Less than 48 hours to following conditions : Patients receiving more than 1 mg/kg/day of prednisone per os Patients receiving methylprednisolone pulse up to 1mg/kg prednisone equivalent (Patients receiving more than 30 grams per day level 3 topical steroid or more than 10 grams per day level 4 topical steroid --> suppressed by amendment 3 : ANSM 28/05/14 CPP : 10/06/14) (Patient undergoing immunosuppressive therapy for another disease suppressed by amendment 5 : ANSM16/04/2015 and CPP 07/04/2015) Participation in another drug biomedical research Primitive bacterial infections, fungal or parasitic Severe rosacea cont-indicating the use of corticosteroid Presence of at least one ulcerated lesion (more than 10cm2) Severe dermatitis perioral cont-indicating the use of corticosteroid Severe acne contra-indicating the use of a corticosteroid Pregnant or nursing women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Corticosteroids per os: Prednisone + Emollient<br> | Drug: Prednisone<br>* Prednisone: Day 0 to day 30: 0.5mg/kg/day Day 30 to day 180: doses decreasing from 15 to 25% every 15 days until Day75 and 10 to 15% every 15 days.<br>|
| Experimental: Topical corticosteroid: Clobetasol + Emollient<br> | Drug: Clobetasol<br>* Clobetasol: cream 0.05% Day 0 to day 30: 30 grams per day Day 30 to day 45: 20 grams per day Day 45 to day 60: 20 grams every other day Day 60 to day 120: 20 grams biweekly Day 120 to day 150: 20 grams one a week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of patients with a complete or almost healing of visceral involvement to D30 +/- 5 days AND complete or almost complete healing of skin involvement. |  | Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of patients with a complete or almost complete healing of cutaneous and visceral involvement at Day 30 ± 5 days |  | Day 30 | 
| Delays of complete or almost complete visceral healing |  | Month 12 | 
| Relapse rates and bounces rates between the end of acute treatment and M12 |  | Month 12 | 
| Patients rate evaluating to severe form (occurrence of a criterion defining the severe form cf. Above) |  | Month 12 | 
| Occurrence rate of moderate DRESS visceral involvement, during the initial treatment (D0 to D30) not existing at inclusion |  | Day 30 | 
| Mortality rate at Month 12 |  | Month 12 | 
| Sequelae rate at Month 12 |  | Month 12 | 
| Systemic steroids adverse reactions rate |  | Month 12 | 
| Topical steroids adverse reactions rate |  | Month 12 | 
| Patch tests evaluation in DRESS |  | Month 6 | 
| Reactivation kinetics of Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes Simplex virus (HSV), Human Herpes virus6 (HHV6) and Human Herpes virus7 (HHV7) |  | Day 0, Day 7, Day 14, Day 21, Day 30, Month 3, Month 6, Month 12 | 
| Predictive value of lymphocyte transformation test in imputability |  | Day 0, Day 30, Month 6, Month 12 | 
| Immunological factors evaluation in the skin |  | Day 30 | 
| Blood inflammatory cytokines and chemokines analysis |  | Day 0, Day 30, Month 6 | 
| Blood cytokines polymorphisms analysis |  | Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DRESS, Systemic steroid, Topical steroid, Treatment