Cyclosporine vs Steroids in DRESS

Sponsor

University of Southern California (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT04988256

Collaborator

(none)

Enrollment

Location

Arms

21.1

Anticipated Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Current treatments for patients with drug reaction with eosinophilia and systemic symptoms (DRESS) include supportive care, steroids and cyclosporine. No randomized controlled trial (RCT) exists in comparing these treatments and all available literature comes in the form of case reports and case series. These two treatments are considered standard of care and this trial seeks only to compare outcomes of DRESS between these two therapies. No additional labs, therapies or procedures will be used apart from those that are routinely done for patients with this diagnosis.

This will be a pilot study to determine efficacy of the two therapies with particular endpoints in mind so that the investigators can study the safety of these two therapies in patients with DRESS.

Data suggests a potential benefit for adults with DRESS using either steroids or cyclosporine but the investigators are seeking a comparison of efficacy of these two therapies. The study population will include adults with a Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) score of greater than 4 (i.e. a likely diagnosis of DRESS). The investigators will exclude patients with sepsis, active Hepatitis B or C, active tuberculosis, a documented allergy to steroids or cyclosporine, and patients with an estimated glomerular filtration rate (eGFR) < 30 (unless on dialysis in which case the participants will be included).

Condition or Disease	Intervention/Treatment	Phase
DRESS Syndrome Drug-Induced Hypersensitivity Syndrome	Drug: Cyclosporine Drug: Methylprednisolone and Prednisone	Early Phase 1

Detailed Description

Current treatments for patients with drug reaction with eosinophilia and systemic symptoms (DRESS) include supportive care, steroids, cyclosporine and to a lesser extent, intravenous immunoglobulin (IVIG). Regarding IVIG, a recent case series suggests no improved benefit in adults. No randomized controlled trial (RCT) exists in comparing these treatments and all available literature comes in the form of case reports and case series. These two treatments are considered standard of care and this trial seeks only to compare outcomes of DRESS between these two therapies. No additional labs, therapies or procedures will be used apart from those that are routinely done for patients with this diagnosis.

This will be a pilot study to determine efficacy of the two therapies with particular endpoints in mind so that the investigators can study the safety of these two therapies in patients with DRESS. Hopefully, this study will allow the investigators to better power a full prospective trial in the future.

This is a potentially life-threatening severe cutaneous adverse reaction (SCAR) with significant potential morbidity. Data suggests a potential benefit for adults with DRESS using either steroids or cyclosporine but the investigators are seeking a comparison of efficacy of these two therapies. The study population will include adults with a Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) score of greater than 4 (i.e. a likely diagnosis of DRESS). The investigators will exclude patients with sepsis, active Hepatitis B or C, active tuberculosis, a documented allergy to steroids or cyclosporine, and patients with an estimated glomerular filtration rate (eGFR) < 30 (unless on dialysis in which case the participants will be included).

Participants will be randomized using a randomization protocol at all sites. Primary endpoints will include percentage of participants with complete or near complete resolution of organ involvement as well as erythema resolution at day 7 and day 30.

Secondary endpoints will be:

fever presence, resolution of facial edema, resolution of pruritus, lymphadenopathy, eosinophil count at days 7 and 30
days of hospitalization
mortality at days 7, 30 and 90
viral reactivation at days 30, 60 and 90
those with autoimmune development by day 30 and day 90
30 day re-admission rate.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Controlled Pilot Trial of Cyclosporine vs Steroids in DRESS

Actual Study Start Date :

Sep 27, 2021

Anticipated Primary Completion Date :

Apr 30, 2023

Anticipated Study Completion Date :

Jun 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Cyclosporine All Patients start with 5 mg/kg/day (3 mg/kg/day if renal impairment) PO divided bid for 7 days (or IV if patient is NPO) If complete resolution, stop cyclosporine and monitor closely for relapse a. If patient relapses, give 5 (3 if renal impairment) mg/kg/day PO divided bid PO for 7 days i. If down-trending, start oral taper regimen ii. If not down-trending, switch to steroid arm If >25% improvement and labs are down-trending, start the oral taper regimen. If 0-25% improvement, give 5 (3 if renal impairment) mg/kg/day PO divided bid for 3 days If down-trending, start oral taper regimen If not down-trending, switch to steroid arm If no improvement or up-trending labs at 7 days, switch to steroid arm Oral Taper Regimen set as 3 mg/kg PO divided bid for 14 days, then 2 mg/kg PO divided bid for 20 days. If renal impairment, oral taper regimen set as 2 mg/kg PO divided bid for 14 days, then 1 mg/kg PO divided bid for 20 days	Drug: Cyclosporine Patients randomized to cyclosporine will be treated as mentioned under "Arm/Group Description"
Experimental: Corticosteroids All Patients start with 500 mg IV Methylprednisolone for 3 days 1. If >25% improvement (must be >25% in all involved organs), start the taper regimen 2. If 0-25% improvement (in ≥1 involved internal organ), give 500 mg IV Methylprednisolone for 4 days If no improvement, switch to cyclosporine arm of treatment If 0-25% improvement, give 500 mg IV Methylprednisolone for 3 days i. If labs are down-trending, start the taper regimen ii. If labs are not down-trending, switch to cyclosporine arm of the study c. If >25% improvement, start the taper regimen Taper Regimen set as: 125 mg IV Methylprednisolone x3 days 1.2 mg/kg PO prednisone x1 week 1 mg/kg PO prednisone x1 week 0.8 mg/kg PO prednisone x1 week 0.6 mg/kg PO prednisone x1 week 0.4 mg/kg PO prednisone x1 week 0.2 mg/kg PO prednisone x1 week 0.1 mg/kg PO prednisone x1 week 0.05 mg/kg PO prednisone x1 week	Drug: Methylprednisolone and Prednisone All patients randomized to steroids will initially be treated with IV methylprednisolone and eventually started on an oral prednisone taper.

Arm

Intervention/Treatment

Active Comparator: Cyclosporine

All Patients start with 5 mg/kg/day (3 mg/kg/day if renal impairment) PO divided bid for 7 days (or IV if patient is NPO) If complete resolution, stop cyclosporine and monitor closely for relapse a. If patient relapses, give 5 (3 if renal impairment) mg/kg/day PO divided bid PO for 7 days i. If down-trending, start oral taper regimen ii. If not down-trending, switch to steroid arm If >25% improvement and labs are down-trending, start the oral taper regimen. If 0-25% improvement, give 5 (3 if renal impairment) mg/kg/day PO divided bid for 3 days If down-trending, start oral taper regimen If not down-trending, switch to steroid arm If no improvement or up-trending labs at 7 days, switch to steroid arm Oral Taper Regimen set as 3 mg/kg PO divided bid for 14 days, then 2 mg/kg PO divided bid for 20 days. If renal impairment, oral taper regimen set as 2 mg/kg PO divided bid for 14 days, then 1 mg/kg PO divided bid for 20 days

Drug: Cyclosporine

Patients randomized to cyclosporine will be treated as mentioned under "Arm/Group Description"

Experimental: Corticosteroids

All Patients start with 500 mg IV Methylprednisolone for 3 days 1. If >25% improvement (must be >25% in all involved organs), start the taper regimen 2. If 0-25% improvement (in ≥1 involved internal organ), give 500 mg IV Methylprednisolone for 4 days If no improvement, switch to cyclosporine arm of treatment If 0-25% improvement, give 500 mg IV Methylprednisolone for 3 days i. If labs are down-trending, start the taper regimen ii. If labs are not down-trending, switch to cyclosporine arm of the study c. If >25% improvement, start the taper regimen Taper Regimen set as: 125 mg IV Methylprednisolone x3 days 1.2 mg/kg PO prednisone x1 week 1 mg/kg PO prednisone x1 week 0.8 mg/kg PO prednisone x1 week 0.6 mg/kg PO prednisone x1 week 0.4 mg/kg PO prednisone x1 week 0.2 mg/kg PO prednisone x1 week 0.1 mg/kg PO prednisone x1 week 0.05 mg/kg PO prednisone x1 week

Drug: Methylprednisolone and Prednisone

All patients randomized to steroids will initially be treated with IV methylprednisolone and eventually started on an oral prednisone taper.

Outcome Measures

Primary Outcome Measures

Percentage of patients with complete or near complete resolution of organ involvement at day 30, on steroid therapy and cyclosporine therapy [Day 7]
Measured by the following quantitative metrics: Creatinine within 1.25x of baseline or upper limit of normal, whichever is higher Aspartate Aminotransferase (AST) within 1.5x of baseline or upper limit of normal, whichever is higher Troponin-T, Creatine Kinase Myocardial Band (CK-MB), Pro B-type Natriuretic Peptide (Pro-BNP), and lipase within 1.25x of baseline or upper limit of normal, whichever is higher Resolution of interstitial pneumonitis on chest x-ray
Percentage of patients with complete or near complete resolution of organ involvement at day 30, on steroid therapy and cyclosporine therapy [Day 30]
Measured by the following quantitative metrics: Creatinine within 1.25x of baseline or upper limit of normal, whichever is higher Aspartate Aminotransferase (AST) within 1.5x of baseline or upper limit of normal, whichever is higher Troponin-T, Creatine Kinase Myocardial Band (CK-MB), Pro B-type Natriuretic Peptide (Pro-BNP), and lipase within 1.25x of baseline or upper limit of normal, whichever is higher Resolution of interstitial pneumonitis on chest x-ray
Percentage of patients with complete or near complete resolution of erythema at day 7, on steroid therapy and cyclosporine therapy [Day 7]
Clinical measurement of erythema
Percentage of patients with complete or near complete resolution of erythema at day 30, on steroid therapy and cyclosporine therapy [Day 30]
Clinical measurement of erythema

Secondary Outcome Measures

Percentage of patients with resolution of fever [Day 7]
Less than 38 degrees Celsius for at least 24 hours
Percentage of patients with resolution of fever [Day 30]
Less than 38 degrees Celsius for at least 24 hours
Percentage of patients with resolution of facial edema [Day 7]
Clinical resolution of edema for at least 24 hours
Percentage of patients with resolution of facial edema [Day 30]
Clinical resolution of edema for at least 24 hours
Percentage of patients with resolution of pruritus [Day 7]
Resolution for at least 24 hours
Percentage of patients with resolution of pruritus [Day 30]
Resolution for at least 24 hours
Percentage of patients with resolution of lymphadenopathy [Day 7]
Clinical resolution of lymphadenopathy for at least 24 hours
Percentage of patients with resolution of lymphadenopathy [Day 30]
Clinical resolution of lymphadenopathy for at least 24 hours
Absolute eosinophil proportion compared to peak value [Day 7]
Proportion of absolute eosinophils
Absolute eosinophil proportion compared to peak value [Day 30]
Proportion of absolute eosinophils
Patients with autoimmune disease development [Day 30]
Measured by titers of autoimmune markers (Antinuclear Antibody (ANA), Thyroid Stimulating Hormone (TSH)) compared to baseline
Patients with autoimmune disease development [Day 90]
Measured by titers of autoimmune markers (Antinuclear Antibody (ANA), Thyroid Stimulating Hormone (TSH)) compared to baseline
Total days of hospitalization after initial dermatology consult [0-120 days]
Number of days
Viral reactivation [Day 30]
Measured by titers of Human Herpesvirus 6 (HHV6), Cytomegalovirus (CMV), and Epstein-Barr Virus (EBV)
Viral reactivation [Day 60]
Measured by titers of Human Herpesvirus 6 (HHV6), Cytomegalovirus (CMV), and Epstein-Barr Virus (EBV)
Viral reactivation [Day 90]
Measured by titers of Human Herpesvirus 6 (HHV6), Cytomegalovirus (CMV), and Epstein-Barr Virus (EBV)
Mortality [Day 7]
Proportion of patient mortality
Mortality [Day 30]
Proportion of patient mortality
Mortality [Day 90]
Proportion of patient mortality
30-day readmission rate [Day 30]
Proportion of patients re-admitted to the hospital within 30 days of discharge

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adults with a RegiSCAR score of greater than 4 (i.e a likely diagnosis of DRESS)

Exclusion Criteria:

Active sepsis
Active hepatitis B or C
Active tuberculosis
Documented allergy to steroids or cyclosporine
Estimated glomerular filtration rate (eGFR) < 30 (unless on dialysis, in which case they will be included)