Clinical trial NCT01987076: Comparison Between Corticosteroid and Topical Steroids in the DRESS
Official title: DRESS - Setting of Corticosteroid Treatment.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Drug Rash With Eosinophilia and Systemic Symptoms
Keywords: DRESS
Systemic steroid
Topical steroid
Treatment
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2013-11-19
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* patient age ≥ 18 years
* signing informed consent form
* DRESS diagnosis with at least 4 criteria a, b, c, d

  1. 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)
  2. Fever ≥ 38 ° at the time of examination or fever ≥ 38.5 ° peak in the last 72 hours (amendment 2 : ANSM + CPP : 08/04/14)
  3. 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

Primary outcomes:
measure: 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.
timeFrame: Day 30
Secondary outcomes:
measure: Rate of patients with a complete or almost complete healing of cutaneous and visceral involvement at Day 30 ± 5 days
timeFrame: Day 30
measure: Delays of complete or almost complete visceral healing
timeFrame: Month 12
measure: Relapse rates and bounces rates between the end of acute treatment and M12
timeFrame: Month 12
measure: Patients rate evaluating to severe form (occurrence of a criterion defining the severe form cf. Above)
timeFrame: Month 12
measure: Occurrence rate of moderate DRESS visceral involvement, during the initial treatment (D0 to D30) not existing at inclusion
timeFrame: Day 30
measure: Mortality rate at Month 12
timeFrame: Month 12
measure: Sequelae rate at Month 12
timeFrame: Month 12
measure: Systemic steroids adverse reactions rate
timeFrame: Month 12
measure: Topical steroids adverse reactions rate
timeFrame: Month 12
measure: Patch tests evaluation in DRESS
timeFrame: Month 6
measure: Reactivation kinetics of Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes Simplex virus (HSV), Human Herpes virus6 (HHV6) and Human Herpes virus7 (HHV7)
timeFrame: Day 0, Day 7, Day 14, Day 21, Day 30, Month 3, Month 6, Month 12
measure: Predictive value of lymphocyte transformation test in imputability
timeFrame: Day 0, Day 30, Month 6, Month 12
measure: Immunological factors evaluation in the skin
timeFrame: Day 30
measure: Blood inflammatory cytokines and chemokines analysis
timeFrame: Day 0, Day 30, Month 6
measure: Blood cytokines polymorphisms analysis
timeFrame: Month 12
Other outcomes:
Locations:
city: Creteil
country: France
facility: Henri Mondor Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Olivier CHOSIDOW, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eshki M, Allanore L, Musette P, Milpied B, Grange A, Guillaume JC, Chosidow O, Guillot I, Paradis V, Joly P, Crickx B, Ranger-Rogez S, Descamps V. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure. Arch Dermatol. 2009 Jan;145(1):67-72. doi: 10.1001/archderm.145.1.67.
citation: Mardivirin L, Valeyrie-Allanore L, Branlant-Redon E, Beneton N, Jidar K, Barbaud A, Crickx B, Ranger-Rogez S, Descamps V. Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro. Eur J Dermatol. 2010 Jan-Feb;20(1):68-73. doi: 10.1684/ejd.2010.0821. Epub 2009 Oct 12.
citation: Funck-Brentano E, Duong TA, Bouvresse S, Bagot M, Wolkenstein P, Roujeau JC, Chosidow O, Valeyrie-Allanore L. Therapeutic management of DRESS: a retrospective study of 38 cases. J Am Acad Dermatol. 2015 Feb;72(2):246-52. doi: 10.1016/j.jaad.2014.10.032.