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

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ClinicalTrials.gov Identifier: NCT01276314
Recruitment Status : Completed
First Posted : January 13, 2011
Results First Posted : December 19, 2017
Last Update Posted : December 19, 2017
Sponsor:
Collaborator:
National Science Council, Taiwan
Information provided by (Responsible Party):
Chang Gung Memorial Hospital

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Drug Hypersensitivity
Interventions Drug: anti- TNF-a
Drug: Prednisolone
Enrollment 135
Recruitment Details SCAR patients were enrolled in the clinical trial from 2009 to 2015 at Chang Gung Memorial Hospital in Taiwan.
Pre-assignment Details We totally recruited 140 participants, but only 135 SCAR participants (including 91 SJS/TEN patients and 44 DRESS patients) were enrolled to analyze. 5 participants in the control group were not included to analyze (3 cases failed a screening with CD4<200 cells/mm3 and 2 cases as diagnosis change).
Arm/Group Title Anti- TNF-a Treatment (SJS/TEN) Control Group (SJS/TEN) Anti- TNF-a Treatment (DRESS) Control Group (DRESS)
Hide Arm/Group Description
  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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

anti-TNF a: 25mg BIW, SC

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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.

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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

anti-TNF a: 25mg BIW, SC

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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.

Period Title: Overall Study
Started 48 43 22 22
Completed 38 33 18 17
Not Completed 10 10 4 5
Arm/Group Title Anti- TNF-a Treatment (SJS/TEN) Control Group (SJS/TEN) Anti- TNF-a Treatment (DRESS) Control Group (DRESS) Total
Hide Arm/Group Description
  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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

anti-TNF a: 25mg BIW, SC

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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.

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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

anti-TNF a: 25mg BIW, SC

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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.

Total of all reporting groups
Overall Number of Baseline Participants 48 43 22 22 135
Hide Baseline Analysis Population Description
A total of 135 SCAR patients (including 91 SJS/TEN cases and 44 DRESS cases) were enrolled to analyze.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 48 participants 43 participants 22 participants 22 participants 135 participants
<=18 years
1
   2.1%
5
  11.6%
0
   0.0%
0
   0.0%
6
   4.4%
Between 18 and 65 years
35
  72.9%
15
  34.9%
17
  77.3%
11
  50.0%
78
  57.8%
>=65 years
12
  25.0%
23
  53.5%
5
  22.7%
11
  50.0%
51
  37.8%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 48 participants 43 participants 22 participants 22 participants 135 participants
52.73  (16.78) 59.84  (24.20) 53.95  (17.41) 60.95  (20.39) 56.53  (20.20)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 48 participants 43 participants 22 participants 22 participants 135 participants
Female
28
  58.3%
23
  53.5%
14
  63.6%
15
  68.2%
80
  59.3%
Male
20
  41.7%
20
  46.5%
8
  36.4%
7
  31.8%
55
  40.7%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Taiwan Number Analyzed 48 participants 43 participants 22 participants 22 participants 135 participants
48
 100.0%
43
 100.0%
22
 100.0%
22
 100.0%
135
 100.0%
1.Primary Outcome
Title Skin Healing Time
Hide Description Healing was defined as complete re-epithelialization (i.e., the complete absence of erosions). We recorded the time taken by the skin to heal.
Time Frame One to two months for SJS/TEN cases, and one to six months for DRESS cases.
Hide Outcome Measure Data
Hide Analysis Population Description
We determined if the enrolled participants had SJS/TEN and DRESS using the criteria and histopathological examinations.
Arm/Group Title Anti- TNF-a Treatment (SJS/TEN) Control Group (SJS/TEN) Anti- TNF-a Treatment (DRESS) Control Group (DRESS)
Hide Arm/Group Description:
  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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

anti-TNF a: 25mg BIW, SC

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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.

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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

anti-TNF a: 25mg BIW, SC

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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.

Overall Number of Participants Analyzed 38 33 18 17
Median (Full Range)
Unit of Measure: days
13.75
(4 to 41)
19
(7 to 42)
40.5
(18 to 117)
34
(9 to 165)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Anti- TNF-a Treatment (SJS/TEN), Control Group (SJS/TEN)
Comments For evaluating the time taken to heal skin erosion, the Kaplan-Meier product-limit estimates method was performed. Differences were considered statistically significant at P values of less than 0.05.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01
Comments The p-value was analyzed for SJS/TEN participants with >10% body surface area detachment.
Method Kaplan-Meier analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Anti- TNF-a Treatment (DRESS), Control Group (DRESS)
Comments For evaluating the time taken to heal skin erosion, the Kaplan-Meier product-limit estimates method was performed. Differences were considered statistically significant at P values of less than 0.05.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.06
Comments This p-value was analyzed for DRESS participants.
Method Kaplan-Meier analysis
Comments [Not Specified]
Time Frame one to two months
Adverse Event Reporting Description The endpoints of serious adverse event and adverse event were assessed for three weeks after discharge.
 
Arm/Group Title Anti- TNF-a Treatment (SJS/TEN) Control Group (SJS/TEN) Anti- TNF-a Treatment (DRESS) Control Group (DRESS)
Hide Arm/Group Description
  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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

anti-TNF a: 25mg BIW, SC

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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.

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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

anti-TNF a: 25mg BIW, SC

  1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
  2. Fill out the case report form
  3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
  4. 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.

All-Cause Mortality
Anti- TNF-a Treatment (SJS/TEN) Control Group (SJS/TEN) Anti- TNF-a Treatment (DRESS) Control Group (DRESS)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Anti- TNF-a Treatment (SJS/TEN) Control Group (SJS/TEN) Anti- TNF-a Treatment (DRESS) Control Group (DRESS)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/48 (10.42%)      9/43 (20.93%)      2/22 (9.09%)      5/22 (22.73%)    
Gastrointestinal disorders         
Upper GI hemorrhage   0/48 (0.00%)  0 1/43 (2.33%)  1 1/22 (4.55%)  1 2/22 (9.09%)  2
Infections and infestations         
Sepsis   2/48 (4.17%)  2 4/43 (9.30%)  4 0/22 (0.00%)  0 2/22 (9.09%)  2
Metabolism and nutrition disorders         
Hyperglycemia   0/48 (0.00%)  0 0/43 (0.00%)  0 0/22 (0.00%)  0 1/22 (4.55%)  1
Psychiatric disorders         
Bipolar disorder   1/48 (2.08%)  1 0/43 (0.00%)  0 0/22 (0.00%)  0 0/22 (0.00%)  0
Reproductive system and breast disorders         
Stridor, vocal cord palsy   0/48 (0.00%)  0 1/43 (2.33%)  1 0/22 (0.00%)  0 0/22 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Respiratory failure   3/48 (6.25%)  3 5/43 (11.63%)  5 1/22 (4.55%)  1 0/22 (0.00%)  0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Anti- TNF-a Treatment (SJS/TEN) Control Group (SJS/TEN) Anti- TNF-a Treatment (DRESS) Control Group (DRESS)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   15/48 (31.25%)      19/43 (44.19%)      8/22 (36.36%)      8/22 (36.36%)    
Gastrointestinal disorders         
GI hemorrhage (grade 2)   1/48 (2.08%)  1 6/43 (13.95%)  6 1/22 (4.55%)  1 3/22 (13.64%)  3
Metabolism and nutrition disorders         
Hyperglycemia   8/48 (16.67%)  8 8/43 (18.60%)  8 4/22 (18.18%)  4 3/22 (13.64%)  3
Vascular disorders         
Hypertension   6/48 (12.50%)  6 5/43 (11.63%)  5 3/22 (13.64%)  3 2/22 (9.09%)  2
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Drug Hypersensitivity Clinical and Research Center, Laboratory of Dr. Wen-Hung Chung,
Organization: Chang Gung Memorial Hospital, Linko
Phone: 886-3-328-1200 ext 8494
Responsible Party: Chang Gung Memorial Hospital
ClinicalTrials.gov Identifier: NCT01276314     History of Changes
Other Study ID Numbers: 97-1413A3
First Submitted: July 5, 2009
First Posted: January 13, 2011
Results First Submitted: November 3, 2017
Results First Posted: December 19, 2017
Last Update Posted: December 19, 2017