APEX-STROKE CALM-ICH Domain

Phase 3Not Yet RecruitingNCT07752719

Fudan University1,100 enrolled

Overview

In this domain of APEX-STROKE, participants with acute intracerebral hemorrhage (ICH) who meet the eligibility criteria for this domain will be randomized in a 1:1 ratio to receive either Angong Niuhuang pills (ANP) or matching placebo, both in addition to guideline-based standard care. The matching placebo is the control condition and is not counted as a domain intervention. • Intervention: Angong Niuhuang pills (ANP) in addition to guideline-based standard care. ANP should be initiated as soon as possible after randomization in the ambulance or emergency department setting, with subsequent treatment continued for a total of 14 days according to the domain-specific intervention schedule. • Control condition: matching placebo in addition to guideline-based standard care.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

1,100

Conditions

Stroke Intracerebral Hemorrhage

Interventions

Angong Niuhuang pills (ANP), a Traditional Chinese Medicine formulation supplied as 3 g pills, administered in addition to guideline-based standard care. Awake participants receive one pill orally as soon as possible after randomization. Unconscious participants receive a suspension prepared by removing the pill shell and grinding it with 15 mL room-temperature normal saline (used within 1 hour of preparation): in the ambulance setting, administered onto the tongue in 2-2.5 mL increments every 10 minutes, with the remaining dose given via nasogastric tube after hospital admission; in the emergency department, administered directly via nasogastric tube. After the initial dose, treatment continues as one pill twice daily during week 1 and one pill once daily during week 2, for a total treatment duration of 14 days.

PlaceboDRUG

Matching placebo, identical to Angong Niuhuang pills (ANP) in appearance, smell, taste, dosing schedule, and treatment duration (14 days total). Contains inactive excipients only and is indistinguishable from active treatment to participants, treating teams, outcome assessors, and trial personnel.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria * In-Hospital Setting 1. Age ≥18 years. 2. Symptom onset or last known well ≤6 hours before randomization. Intracerebral hemorrhage (ICH) confirmed by brain imaging, with a hematoma volume ≥10 mL. 3. National Institutes of Health Stroke Scale (NIHSS) score ≥8. 4. Glasgow Coma Scale (GCS) score ≥8. 5. Traditional Chinese medicine (TCM) syndrome consistent with internal accumulation of heat-toxin, defined by the presence of at least 2 of the following: high fever, facial flushing, agitation, dry mouth, and rapid pulse. 6. No surgery performed at the time of randomization. 7. Written informed consent obtained from the participant or their legally authorized representative. * Prehospital (Ambulance) Setting 1. Age ≥18 years. 2. Symptom onset or last known well ≤6 hours before randomization. 3. Predicted to have ICH by an artificial intelligence-based model. 4. FAST score ≥2. 5. TCM syndrome consistent with internal accumulation of heat-toxin, defined by the presence of at least 2 of the following: high fever, facial flushing, agitation, dry mouth, and rapid pulse. 6. Written informed consent obtained from the participant or their legally authorized representative. Exclusion Criteria * In-Hospital Setting 1. Secondary ICH, including ICH associated with cerebrovascular malformations or other structural abnormalities, brain tumors, head trauma, hemorrhagic transformation of cerebral infarction, or bleeding following thrombolysis or thrombectomy. 2. Severe comorbidities that may interfere with study treatment, follow-up, or outcome assessment (e.g., severe heart failure, malignant tumors, chronic obstructive pulmonary disease, or severe pre-existing disability). 3. Known allergy to Angong Niuhuang Wan or any of its ingredients. 4. Pregnancy or breastfeeding. 5. History of severe chronic kidney disease or hepatic failure. 6. Very high likelihood of death within 7 days or poor anticipated adherence to study treatment or follow-up. * Prehospital (Ambulance) Setting 1. Blood glucose \<2.8 mmol/L. 2. History of head trauma within the previous 7 days. 3. History of seizures or seizure-like episodes. 4. Severe comorbidities that may interfere with study treatment, follow-up, or outcome assessment (e.g., severe heart failure, malignant tumors, chronic obstructive pulmonary disease, or severe pre-existing disability). 5. Known allergy to Angong Niuhuang Wan or any of its ingredients. 6. Pregnancy or breastfeeding. 7. History of severe chronic kidney disease or hepatic failure. 8. Very high likelihood of death within 7 days or poor anticipated adherence to study treatment or follow-up.

Outcomes

Primary Outcomes

modified Rankin scale (mRS) scores

The modified Rankin Scale (mRS) is a 7-point ordinal scale assessing global disability and functional dependence after stroke, ranging from 0 (no symptoms) to 6 (death). Intermediate scores indicate increasing severity: 1, no significant disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability. The primary analysis will use the ordinal distribution of scores across all 7 levels; lower scores indicate better functional outcome.

Time frame: 180 days

Secondary Outcomes

Hematoma volume

Hematoma volume will be measured on brain CT/MRI in mL using semi-automated volumetric software.

Time frame: 24 hours

Hematoma Expansion at 24 Hours

Hematoma expansion is defined as an absolute increase of ≥6 mL or a relative increase of ≥33% in hematoma volume between baseline and the 24-hour scan.

Time frame: 24 hours

NIHSS score

The National Institutes of Health Stroke Scale (NIHSS) ranges from 0 (no neurological deficit) to 42 (most severe deficit), assessing consciousness, gaze, visual fields, motor and sensory function, language, and neglect. Higher scores indicate more severe neurological impairment.

Time frame: 24 hours and 7 day

Mortality

All-cause mortality will be reported as the number and proportion of participants who died from any cause by 180 days after randomization.

Time frame: 180 days

Favorable functional outcome (mRS 0-2 and mRS 0-3)

Favorable functional outcome is defined using the modified Rankin Scale (mRS), which ranges from 0 (no symptoms) to 6 (death). Two thresholds will be reported: participants achieving mRS 0-2 (no symptoms to slight disability, independent living) and participants achieving mRS 0-3 (no symptoms to moderate disability, ambulatory without assistance).

Time frame: 180 days

Health-Related quality of Life assessed by EQ-5D

The EQ-5D assesses health-related quality of life across 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each scored on a severity scale, combined into a weighted index value, with an accompanying EQ visual analogue scale (EQ-VAS) rated from 0 (worst imaginable health) to 100 (best imaginable health). Higher scores indicate better health status.

Time frame: 180 days