Severe Erythema Multiforme - CORTICO

Official title

Severe Erythema Multiforme: A Randomized Controlled Trial Comparing a Short Systemic Corticosteroids Regimen to Placebo in the Acute Established Phase

Overview

Erythema multiforme (EM) is an acute and often recurrent mucocutaneous disease. EM is considered a hypersensitivity immune-mediated reaction. The two main known triggering factors are Herpes simplex virus (HSV) and Mycoplasma pneumoniae (MP) infections. Typical target skin lesions characterize EM, especially oral MMs. EM is in fact mainly linked to the oral MM involvement, including intense mucosal pain, impaired food intake, weight loss, hospitalization and potential risk of fibrotic sequelae (oral, ocular, genital, oesophageal, respiratory tract) and recurrences. The objectives of treatment for severe EM in the acute phase are to reduce the duration of lesions, prevent complications and mucosal sequelae. However, despite the lack of evidence and consensus some medical teams often use a short regimen of SCS hoping to obtain a quicker improvement of the condition. However, the use of SCS at the acute phase is not codified and remains debated according to the existent literature. Current studies are mostly retrospective and based on small cohorts or case reports. A randomized, controlled trial would be therefore essential to properly evaluate the benefit of SCS in this pathology and provide strong support to clinicians in their decision making in severe EM during the acute phase. This research will be a Phase III randomized, multicentric, double-blind, controlled trial with two parallel groups. The efficacy of prednisone, oral at 1 mg/kg/day for 3 days, tapered to 0.75 mg/kg/day for 3 days, 0.50 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days is compared to that of placebo, oral for 12 days or IV methylprednisolone if oral route is impossible because of the self-reported inability for the patient to swallow due to the impacts of the oral lesions, with dosage equivalence at 0.8 mg/kg/day for 3 days, tapered to 0.6 mg/kg/day for 3 days, 0.4 mg/kg/day for 3 days, 0.2 mg/kg/day for 3 days, then stopped, compared to that of placebo. A stratification according to the food intake classification (0,1,2 vs 3) will be performed. An interim analysis is planned after the inclusion of 50 patients. Results of the interim analysis will be presented to the DSMB. During the interim analysis, inclusions may continue.

Interventions

• Drug Prednisone 20 Mg
  Oral corticosteriods
• Drug Oral Placebo
  Oral placebo
• Drug Methylprednisolone 120 Mg
  IV corticosteriods
• Drug IV Placebo
  IV placebo

Primary outcome measures

• Time to success [Time frame: Day0 to Month1]
• Evaluation of Pain [Time frame: Day0 to Month1]
• Food intake [Time frame: Day0 to Month1]
• Rescue therapy intake [Time frame: From Day 0 until discharge from hospital, assessed up to Day 15]

Secondary outcome measures (10)

• Time to clear or almost clear healing of all sites [Time frame: Day15 and Month1]
• Time to fever resolution [Time frame: From Day 0 until discharge from hospital, assessed up to Day 15]
• Length of hospital stay [Time frame: From Day 0 until discharge from hospital, assessed up to Day 15]
• Number of days of consumption of level III analgesics [Time frame: From Day 0 until complete healing, assessed up to Month 1]
• Evaluation of pain [Time frame: From Day 0 until complete healing, assessed up to Month 1]
• Chopped or solid food intake resumption [Time frame: From Day 0 until complete healing, assessed up to Month]
• Rate of patients in the two groups with need for a rescue therapy [Time frame: From Day 0 until discharge from hospital, assessed up to Day 15]
• Rate of sequelae [Time frame: Month3 and Month6]
• Rate of adverse events during the treatment and follow-up [Time frame: Day0 to Month6]
• Evaluation of the quality of life [Time frame: at the end of hospitalization, Day7, Day15 and Month1 and in case of relapse]

Eligibility criteria

Inclusion criteria

• Age ≥ 15 years old and 30 kg ≤ Weight ≤ 150 kg
• Clinical diagnosis of severe EM defined as:

• Typical skin lesions if first flare of EM: raised target lesions with 2 or 3 concentric rings located on the extremities or disseminated. In case of recurrent EM, with proven anterior flare (known clinical diagnosis as-sociating typical skin lesions and MM involvement in a previous flare), typical skin lesions are not essential for inclusion, because EM may manifest as isolated mucosal involvement.
• Two or more MMs affected (mouth, throat, eyes, ear, nose, genital and/or anal areas), or only the oral MM affected, if severely affected (score\* 2 or 3 of Harman criteria22) with altered general conditions and significant impact on food intake (solid food impossible)
• First flare of EM or acute recurrence of previously diagnosed EM
• Disease flare that has lasted for up to 5 days (≤5 days)
• Affiliated to a social security scheme
• Able to provide written informed consent; consent of both parents will be col-lected for minors

• score: 1, minor activity (up to three erosions); 2, moderate activity (more than three but less than 10 erosions, or generalized desquamative gingivitis); 3, severe (more than 10 discrete erosions or extensive, confluent erosions, or generalized desquamative gingivi-tis with discrete erosions at other oral sites).

Exclusion criteria

• EM without involvement of oral cavity compromising normal solid food
• Patients unable to eat solid food outside of their current pathology (erythema multiforme)
• Other diagnosis potentially involving MMs: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), pemphigus, herpetic gingivostomatitis
• Systemic Corticosteroids prescribed for another disease on inclusion day (any dose)
• Use of systemic Corticosteroids for > 5 days for any previous flare of EM (>10mg),
• Contraindication to systemic Corticosteroids:

• hypersensitivity to systemic Corticosteroids or to an excipient;
• uncontrolled primary bacterial, viral, fungal or parasitic infection
• psychotic states not yet controlled by treatment
• Sepsis (shock, cyanosis, hypothermia, low blood pressure monitored succes-sively twice (systemic blood pressure < 90 mmHg and diastolic blood pres-sure < 60 mmHg)
• Kidney or liver insufficiency (creatinine level ≥ 150 µmol/L; aspartate ami-notransferase or alanine aminotransferase level > 3 times the upper limit of normal)
• Current cancer with the exception of non-metastatic skin carcinoma not re-quiring immediate medical treatment
• Pregnant or breastfeeding
• Person subject to safeguards of justice
• Person deprived of liberty by judicial or administrative decision
• Person subject to psychiatric care without their consent
• Person admitted to a health or social establishment for purposes other than those of research
• Person unable to express their consent
• Person under legal protection (guardianship or curatorship)
• Participation in another interventional study involving human participants or in the exclusion period at the end of a previous study involving human partici-pants, if applicable
• On state medical aid

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06266221 · APHP200073 · 2022-000712-59

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗