Comparison Between Corticosteroid and Topical Steroids in the DRESS (DRESSCODE)
Primary Purpose
Drug Rash With Eosinophilia and Systemic Symptoms
Status
Unknown status
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Prednisone
Clobetasol
Sponsored by
About this trial
This is an interventional treatment trial for Drug Rash With Eosinophilia and Systemic Symptoms focused on measuring DRESS, Systemic steroid, Topical steroid, Treatment
Eligibility Criteria
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
Sites / Locations
- Henri Mondor HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
Corticosteroids per os: Prednisone + Emollient
Topical corticosteroid: Clobetasol + Emollient
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Rate of patients with a complete or almost complete healing of cutaneous and visceral involvement at Day 30 ± 5 days
Delays of complete or almost complete visceral healing
Relapse rates and bounces rates between the end of acute treatment and M12
Patients rate evaluating to severe form (occurrence of a criterion defining the severe form cf. Above)
Occurrence rate of moderate DRESS visceral involvement, during the initial treatment (D0 to D30) not existing at inclusion
Mortality rate at Month 12
Sequelae rate at Month 12
Systemic steroids adverse reactions rate
Topical steroids adverse reactions rate
Patch tests evaluation in DRESS
Reactivation kinetics of Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes Simplex virus (HSV), Human Herpes virus6 (HHV6) and Human Herpes virus7 (HHV7)
Predictive value of lymphocyte transformation test in imputability
Immunological factors evaluation in the skin
Blood inflammatory cytokines and chemokines analysis
Blood cytokines polymorphisms analysis
Full Information
NCT ID
NCT01987076
First Posted
September 17, 2013
Last Updated
July 29, 2015
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT01987076
Brief Title
Comparison Between Corticosteroid and Topical Steroids in the DRESS
Acronym
DRESSCODE
Official Title
DRESS - Setting of Corticosteroid Treatment.
Study Type
Interventional
2. Study Status
Record Verification Date
July 2015
Overall Recruitment Status
Unknown status
Study Start Date
October 2013 (undefined)
Primary Completion Date
October 2015 (Anticipated)
Study Completion Date
October 2016 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Drug Rash With Eosinophilia and Systemic Symptoms
Keywords
DRESS, Systemic steroid, Topical steroid, Treatment
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
112 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Corticosteroids per os: Prednisone + Emollient
Arm Type
Active Comparator
Arm Title
Topical corticosteroid: Clobetasol + Emollient
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Prednisone
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Clobetasol
Intervention Description
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
Primary Outcome Measure Information:
Title
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.
Time Frame
Day 30
Secondary Outcome Measure Information:
Title
Rate of patients with a complete or almost complete healing of cutaneous and visceral involvement at Day 30 ± 5 days
Time Frame
Day 30
Title
Delays of complete or almost complete visceral healing
Time Frame
Month 12
Title
Relapse rates and bounces rates between the end of acute treatment and M12
Time Frame
Month 12
Title
Patients rate evaluating to severe form (occurrence of a criterion defining the severe form cf. Above)
Time Frame
Month 12
Title
Occurrence rate of moderate DRESS visceral involvement, during the initial treatment (D0 to D30) not existing at inclusion
Time Frame
Day 30
Title
Mortality rate at Month 12
Time Frame
Month 12
Title
Sequelae rate at Month 12
Time Frame
Month 12
Title
Systemic steroids adverse reactions rate
Time Frame
Month 12
Title
Topical steroids adverse reactions rate
Time Frame
Month 12
Title
Patch tests evaluation in DRESS
Time Frame
Month 6
Title
Reactivation kinetics of Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes Simplex virus (HSV), Human Herpes virus6 (HHV6) and Human Herpes virus7 (HHV7)
Time Frame
Day 0, Day 7, Day 14, Day 21, Day 30, Month 3, Month 6, Month 12
Title
Predictive value of lymphocyte transformation test in imputability
Time Frame
Day 0, Day 30, Month 6, Month 12
Title
Immunological factors evaluation in the skin
Time Frame
Day 30
Title
Blood inflammatory cytokines and chemokines analysis
Time Frame
Day 0, Day 30, Month 6
Title
Blood cytokines polymorphisms analysis
Time Frame
Month 12
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Olivier CHOSIDOW, MD, PhD
Phone
(0) 149812501
Ext
+33
Email
olivier.chosidow@hmn.aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
: Laurence ALLANORE, MD
Phone
(0) 149812501
Ext
+33
Email
laurence.allanore@hmn.aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Olivier CHOSIDOW, MD, PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Henri Mondor Hospital
City
Creteil
ZIP/Postal Code
94010
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Olivier CHOSIDOW, MD, PhD
Phone
(0)149812501
Ext
+33
Email
olivier.chosidow@hmn.aphp.fr
First Name & Middle Initial & Last Name & Degree
Laetitia GREGOIRE, M.Sc
Phone
(0)149814164
Ext
+33
Email
laetitia.gregoire@hmn.aphp.fr
First Name & Middle Initial & Last Name & Degree
Olivier CHOSIDOW, MD, PhD
12. IPD Sharing Statement
Citations:
PubMed Identifier
19153346
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.
Results Reference
background
PubMed Identifier
19822481
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.
Results Reference
background
PubMed Identifier
25592341
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.
Results Reference
derived
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Comparison Between Corticosteroid and Topical Steroids in the DRESS
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