Evaluation of TNF-α Blockade Effect in Patients With Severe Cutaneous Adverse Drug Reactions

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

Severe skin adverse drug reactions can result in death. Toxic epidermal necrolysis (TEN) has the highest mortality (30-35%); Stevens-Johnson syndrome and transitional forms correspond to the same syndrome, but with less extensive skin detachment and a lower mortality (5-15%). Hypersensitivity syndrome, sometimes called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), has a mortality rate evaluated at about 10%. The aims of this project are (1) to compare the effect of treatment between systemic steroid and anti-TNF-α. Including skin healing time, beginning of re-epithelialization time, internal organ recovery time, mortality rate, adverse events and (2) to investigate the molecular mechanism of severe cutaneous adverse reaction after anti-TNF-α treatment.

Condition or disease	Intervention/treatment	Phase
Drug Hypersensitivity	Drug: anti- TNF-a; Drug: Prednisolone	Not Applicable

Detailed Description:

Severe cutaneous adverse drug reactions, including Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome(SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a life threatening disease. There is no gold standard in the therapy of SCAR. Treatment with high dose systemic corticosteroids is controversial. Although there have been recent reports of success with various therapies such as plasmapheresis and high-dose intravenous immunoglobulins, their efficacy is not yet proven. Assessment of these therapies is difficult because of their non-specific immunosuppressant or immunomodulating modes of action. Recent studies have shown evidence of the pathogenetic importance of tumour necrosis factor (TNF)-a, suggesting a new therapeutic approach in selective blockade of TNF-a using specific antibodies. We report successful treatment TEN using monoclonal IgG anti-TNF-antibodies. The aims of this project are (1) to compare the effect of treatment between systemic steroid and anti-TNF-α. Including skin healing time, beginning of re-epithelialization time, internal organ recovery time, mortality rate, adverse events and (2) to investigate the molecular mechanism of severe cutaneous adverse reaction after anti-TNF-α treatment.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	135 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Evaluation of TNF-α Blockade Effect in Patients With Severe Cutaneous Adverse Drug Reactions (SCAR)
Study Start Date :	January 2009
Actual Primary Completion Date :	May 2015
Actual Study Completion Date :	May 2015

Arms and Interventions

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Arm	Intervention/treatment
Experimental: anti- TNF-a treatment; Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF; Fill out the case report form; Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis; Etanercept administration: The experimental group received the first dose of Etanercept (25 mg) i.v., followed by two doses per week and maintain 2 to 3 weeks	Drug: anti- TNF-a; 25mg BIW, SC; Other Name: Etanercept
Active Comparator: control group; Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF; Fill out the case report form; Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis; Drug administration: The control group of drug delivery: systemic intravenous steroid therapy, the dose is equivalent to prednisolone 1-1.5 mg / kg / day, according to the treatment of 3-4 days gradually decreased dose.	Drug: Prednisolone; 1-1.5 mg / kg / day; Other Name: steroid therapy

Outcome Measures

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Primary Outcome Measures :

1. Skin Healing Time [ Time Frame: One to two months for SJS/TEN cases, and one to six months for DRESS cases. ]
   Healing was defined as complete re-epithelialization (i.e., the complete absence of erosions). We recorded the time taken by the skin to heal.

Eligibility Criteria

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Ages Eligible for Study:	4 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Male or female patient with clinical and pathological diagnoses of severe cutaneous adverse drug reactions such as Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis or Durg reaction with eosinophilia and systemic symptoms.
2. Male or female patient aged more than 4 years.
3. Inform consent obtained.

Exclusion Criteria:

1. Pregnant or breastfeeding female.
2. Allergic to any anti-TNF-α biological product.
3. Active or latent tuberculosis confirmed with Chest X-ray.
4. Severe active infection and septicemia.
5. Active Hepatitis B or C carrier.
6. Suspected HIV carrier with CD4 count less than 200.
7. Patient with poor compliance or with safety concerns judged by investigator.

Contacts and Locations

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Locations

Taiwan
Department of Dermatology, Chang Gung Memorial hospital
Taipei, Taiwan, 105

Sponsors and Collaborators

Chang Gung Memorial Hospital

National Science Council, Taiwan

Investigators

Study Chair:	Wen-Hung Chung, MD	Department of Dermatology, CGMH

More Information

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Publications of Results:

Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol. 2008 Jan;58(1):33-40. Epub 2007 Oct 4.

Paradisi A, Abeni D, Bergamo F, Ricci F, Didona D, Didona B. Etanercept therapy for toxic epidermal necrolysis. J Am Acad Dermatol. 2014 Aug;71(2):278-83. doi: 10.1016/j.jaad.2014.04.044. Epub 2014 Jun 11.

Other Publications:

Paquet P, Paquet F, Al Saleh W, Reper P, Vanderkelen A, Piérard GE. Immunoregulatory effector cells in drug-induced toxic epidermal necrolysis. Am J Dermatopathol. 2000 Oct;22(5):413-7.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wang CW, Yang LY, Chen CB, Ho HC, Hung SI, Yang CH, Chang CJ, Su SC, Hui RC, Chin SW, Huang LF, Lin YY, Chang WY, Fan WL, Yang CY, Ho JC, Chang YC, Lu CW, Chung WH; and the Taiwan Severe Cutaneous Adverse Reaction (TSCAR) Consortium. Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions. J Clin Invest. 2018 Mar 1;128(3):985-996. doi: 10.1172/JCI93349. Epub 2018 Feb 5.

Responsible Party:	Chang Gung Memorial Hospital
ClinicalTrials.gov Identifier:	NCT01276314 History of Changes
Other Study ID Numbers:	97-1413A3
First Posted:	January 13, 2011
Results First Posted:	December 19, 2017
Last Update Posted:	December 19, 2017
Last Verified:	December 2014

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Chang Gung Memorial Hospital:

SCAR; anti-TNF-a

Additional relevant MeSH terms:

Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Drug Hypersensitivity; Immune System Diseases; Chemically-Induced Disorders; Prednisolone acetate; Methylprednisolone acetate; Prednisolone; Methylprednisolone; Methylprednisolone Hemisuccinate; Etanercept; Prednisolone hemisuccinate; Prednisolone phosphate; Anti-Inflammatory Agents; Glucocorticoids	Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Neuroprotective Agents; Protective Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents