DIROXIMEL FUMARATE TO REDUCE PERIHAEMATOMAL OEDEMA IN INTRACEREBRAL HAEMORRHAGE: DOUBLE BLIND RANDOMIZED CLINICAL TRIAL

Official title

DIROXIMEL FUMARATE TO REDUCE PERIHAEMATOMAL OEDEMA IN INTRACEREBRAL HAEMORRHAGE: A DOUBLE BLIND RANDOMIZED CLINICAL TRIAL (DARLENE)

Overview

Spontaneous intracerebral haemorrhage (ICH) is a life-threatening condition, still devoided of specific treatment. Peri-haematomal oedema (PHO) develops in the ensuing days after ICH onset and worsens functional outcome. Hence, PHO is a promising therapeutic target but until now there is no specific treatment for PHO. The occurrence and growth of PHO is mainly mediated by inflammation. We hypothesize that a modulation of inflammation is effective in reducing PHO growth, therefore improving the functional outcome of ICH patients. From animal studies to human post-mortem studies, our team has demonstrated a key role for erythroid-related nuclear factor 2 (Nrf2) in PHO. Indeed, this transcription factor promotes the protective effect of inflammation: Nrf2 activation enhances antioxidant defenses and increases rates of blood resorption. Therefore, Nrf2 emerges as a promising and innovative therapeutic target. Taking into account the prolonged time interval between de novo drug discovery and use in clinical practice, drug repurposing is an interesting option for the unmet clinical need of reducing PHO. We chose Diroximel Fumarate (DRF) which is a safe and effective Nrf2 activator widely used in multiple sclerosis (dimethyl fumarate is on the market since 2013, and DRF since 2019) to modulate inflammation and to establish the efficacy of Nrf2 activation in reducing PHO growth and, ultimately, in improving the functional prognosis after ICH.

Interventions

• Drug DRF
  2\*231 mg of Diroximel Fumarate (DRF) per day for 7 days then 4\*231 mg per day for 14 days.
• Drug Placebo
  2 capsules of matching placebo per day for 7 days than 4 capsules of matching placebo per day for 14 days.

Primary outcome measures

• Absolute volume of PHO assessed at 8 ± 1 days with brain non-contrast CT (NCCT) scan. [Time frame: at 8 ± 1 days]

Secondary outcome measures (2)

• Functional outcome: global disability assessed by overall distribution of mRS score at 6 months (end of follow-up) (shift analysis) [Time frame: at 6 months]
• The rate of severe adverse events occurring between the date of randomization and the end of follow-up (six-month visit). [Time frame: At 6 months]

Eligibility criteria

Inclusion criteria

• Patients 18 years or older (no upper age limit)
• Patients admitted for a first-ever or recurrent (occurred more than 1 year before) symptomatic supratentorial spontaneous ICH confirmed by brain imaging
• Administration of study treatment no later than 48 hours after symptom onset or since last seen normal
• Written consent obtained
• Patient with social insurance in France
• Patient willing to comply with all study procedures and duration

Exclusion criteria

• Massive ICH for Investigational medicinal product seems futile (hematoma volume is estimated > 60ml)
• Severe coma (Glasgow Coma Scale <6)
• Pure intraventricular hemorrhage
• ICH suspected to result from a preceding trauma, an identified intracranial vascular malformation, venous thrombosis, tumor or hemorrhagic transformation within an infarct
• Patient planned for surgical evacuation of ICH before randomization (Evacuation, Decompressive hemicraniectomy, External ventricular drain)
• Patient with a known indication for DRF treatment (e.g. multiple sclerosis) or any other NrF2 agonist (dimethyl fumarate; Tecfidera)
• Patient with contraindication to DRF: patients with known hypersensitivity to DRF, or to any of the excipients of VUMERITY (patients taking dimethyl fumarate)
• Severe lymphopenia at admission (lymphocyte counts < 0.5 x 109/L)
• Medical history: Suspected or confirmed of progressive multifocal leukoencephalopathy
• Severe swallowing disorder and/or nasogastric tube required
• Severe pre-ICH dependency (modified Rankin score of 5)
• Life expectancy < 1 year related to comorbidities
• Late-stage organ (acute cardiac, renal or hepatic failure)
• Decision already taken for palliative (end of life) care with withdrawal of active treatment
• Pregnancy or breastfeeding or Women of childbearing age without effective contraception (a pregnancy test will be done)
• Adults who are deprived of their liberty by judicial or administrative decision

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

France · 1 center

• CHU de Lille — Lille

Identifiers

NCT: NCT07275515 · 2024_0474 · 2025-522687-33-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗