The Fifth INTEnsive pReventing Secondary Injury in Acute Cerebral Haemorrhage Trial Within ACT-GLOBAL

Intracerebral hemorrhage (ICH) is a severe type of stroke, responsible for substantial disability and death worldwide. It accounts for 6.5% to 19.6% of all strokes, with incidence rates increasing, especially in low- and middle-income countries. Survivors often face significant consequences, including functional impairments, recurrent strokes, cognitive decline, and depression.

Despite advancements in acute stroke care, there are few effective treatments specifically targeting the brain damage caused by ICH. Previous research has identified that the formation of perihaematomal oedema (PHE) is a critical factor in poor recovery, making it a key focus for therapeutic development.

INTERACT5 domain will focus on two promising medications. Deferoxamine, an iron-chelating agent, targets oxidative stress caused by iron released from damaged brain tissue. Studies suggest it may reduce brain swelling and secondary injury after ICH. Colchicine, an anti-inflammatory medication, inhibits pathways involved in inflammation, which may help minimize brain damage. INTERACT5 will enroll patients aged 18-80 with acute spontaneous supratentorial ICH, confirmed through imaging, who present to the hospital within 24 hours of symptom onset. Other domain-specific inclusion criteria:

• Hematoma volume ≥≥10 mL or any volume post-surgery
• NIHSS score >8
• GCS ≥8>7

Participants will be randomized to one of four groups: standard care, deferoxamine alone, colchicine alone, or both treatments combined. Deferoxamine will be administered intravenously (32 mg/kg/day within 1 hour and continued for 2 consecutive days), and colchicine will be given orally (0.5 mg daily for 30 days).

The study's primary outcome is the improvements in functional outcomes at 6 months, measured by the modified Rankin Scale (mRS). Secondary outcomes include EQ-5D-5L at 6 months, changes in PHE size, NIHSS scores, length of hospital stay, ambulatory status at discharge and safety indicators such as mortality at 6 months/SAEs to 6 month, kidney and liver function.

Response Adaptive Randomization (RAR) will be used in this domain to allow readjustment of recruitment towards treatment arms with more favorable emerging effects. Randomization will use minimization method to minimize the imbalance between the number of patients in each treatment group over a number of factors including region, location (deep vs cortical)age (>65 vs ≤65 years old), sex (male vs female), time from onset (>6 vs ≤6 hours), haematoma volume (10-29 vs ≥30 mL), receipt of any decompressive surgery (yes vs no), and intraventricular extension of ICH, etc.

Inclusion criteria

• Age between 18 and 80 years old
• Diagnosis of presumed spontaneous supratentorial intracerebral haemorrhage, confirmed by brain imaging
• Presentation to hospital within 24 hours of symptom onset (or last seen well)
• Hematoma volume ≥10 mL or any volume post-surgery
• NIHSS score >8
• GCS ≥8
• Provide written informed consent by patient (or approved surrogate)

Exclusion criteria

• Secondary cause of haemorrhage (e.g., structural abnormality such as arteriovenous malformation, cerebral aneurysm, tumour, trauma), or haemorrhagic transformation of acute ischaemic stroke
• Isolate intraventricular haemorrhage
• Chronic Kidney Disease
• Very high likelihood of death within 7 days or poor adherence to study treatment or follow-up
• Severe comorbid disease that will interfere with outcome assessments (e.g., cancer, chronic airflow disease, heart failure, significant disability)
• Women who are pregnant or lactating

Exclusion criteria

related to use of deferoxamine:

• Previous chelation therapy or known hypersensitivity to deferoxamine products;
• Severe iron deficiency anaemia (haemoglobin <7 g/dL or requiring regular blood transfusions);
• Taking iron supplements containing >325 mg of ferrous iron;
• Serum creatinine >2 mg/dL;
• Patients with known heart failure taking >500 mg of vitamin C

Exclusion criteria

related to the use of colchicine:

• Allergic to colchicine
• Myelodysplastic hypoplasia, or liver or severe renal failure
• Use of medication which may interact with colchicine (e.g., strong CYPsA4 inhibitors such as ketoconazole, strong P-glycoprotein inhibitors such as fluconazole)