Cyclosporine vs Steroids in DRESS

A Randomized Controlled Pilot Trial of Cyclosporine vs Steroids in DRESS

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).

Study Overview

• Status: Enrolling by invitation
• Conditions: DRESS Syndrome; Drug-Induced Hypersensitivity Syndrome
• Intervention / Treatment: Drug: Cyclosporine; Drug: Methylprednisolone and Prednisone

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:

1. fever presence, resolution of facial edema, resolution of pruritus, lymphadenopathy, eosinophil count at days 7 and 30
2. days of hospitalization
3. mortality at days 7, 30 and 90
4. viral reactivation at days 30, 60 and 90
5. those with autoimmune development by day 30 and day 90
6. 30 day re-admission rate.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 relapsea. If patient relapses, give 5 (3 if renal impairment) mg/kg/day PO divided bid PO for 7 daysi. If down-trending, start oral taper regimenii. 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 daysIf down-trending, start oral taper regimenIf 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with complete or near complete resolution of organ involvement at day 30, on steroid therapy and cyclosporine therapy	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	Day 7
Percentage of patients with complete or near complete resolution of organ involvement at day 30, on steroid therapy and cyclosporine therapy	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	Day 30
Percentage of patients with complete or near complete resolution of erythema at day 7, on steroid therapy and cyclosporine therapy	Clinical measurement of erythema	Day 7
Percentage of patients with complete or near complete resolution of erythema at day 30, on steroid therapy and cyclosporine therapy	Clinical measurement of erythema	Day 30

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Southern California

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2021
• Primary Completion (Estimated): April 30, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: June 24, 2021
• First Submitted That Met QC Criteria: July 31, 2021
• First Posted (Actual): August 3, 2021

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Skin Diseases; Immune System Diseases; Disease; Dermatitis; Drug-Related Side Effects and Adverse Reactions; Hypersensitivity, Delayed; Drug Eruptions; Drug Hypersensitivity; Hypersensitivity; Syndrome; Drug Hypersensitivity Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Methylprednisolone; Prednisone; Cyclosporine; Cyclosporins
• Other Study ID Numbers: HS-20-00118

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No