APEX-STROKE CALM-ICH Domain (CALM-ICH)

Chinese Angong Niuhuang for Acute Medical Management of Intracerebral Hemorrhage (CALM-ICH) Domain of the APEX-STROKE Adaptive Platform Trial

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 Overview

• Status: Not yet recruiting
• Conditions: Stroke; Intracerebral Hemorrhage
• Intervention / Treatment: Drug: Angong Niuhuang Pills (ANP); Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 1100
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early Angong Niuhuang Pill (ANP) treatment; Participants in this arm receive early treatment with ANP Within 6 hours of onset.	Drug: Angong Niuhuang Pills (ANP); 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.
Placebo Comparator: Placebo; Participants in this arm will not receive ANP and will receive a matching placebo.	Drug: Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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).	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.	180 days
Hematoma volume	Hematoma volume will be measured on brain CT/MRI in mL using semi-automated volumetric software.	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.	24 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Serious Adverse Events	Incidence of serious adverse events (SAEs) occurring during the safety follow-up period. An SAE is defined as an adverse event resulting in death, a life-threatening event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, or an important medical event that, based on appropriate medical judgment, may jeopardize the participant or require medical or surgical intervention to prevent one of these outcomes.	From randomization through 180 days after randomization
Incidence of Adverse Events of Special Interest	Incidence of adverse events of special interest (AESIs) during the safety follow-up period. AESIs include whole-blood mercury or arsenic concentrations ≥2 times the upper limit of normal (ULN), liver function abnormalities defined as alanine aminotransferase or aspartate aminotransferase >3 times the ULN, and renal function abnormalities defined as serum creatinine ≥2 mg/dL.	From randomization through 180 days after randomization

Collaborators and Investigators

• Sponsor: Fudan University
• Collaborators: Guangdong Provincial Hospital of Traditional Chinese Medicine; Chinese PLA General Hospital; Huashan Hospital; Beijing University of Chinese Medicine; Hubei College of Traditional Chinese Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): January 31, 2029
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: July 27, 2026
• First Submitted That Met QC Criteria: August 4, 2026
• First Posted (Actual): August 7, 2026

Study Record Updates

• Last Update Posted (Actual): August 26, 2026
• Last Update Submitted That Met QC Criteria: August 24, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Hemorrhage; Intracranial Hemorrhages; Pathological Conditions, Signs and Symptoms; Stroke; Cerebral Hemorrhage; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Health Services Administration; Health Care Quality, Access, and Evaluation; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Quality of Health Care; Quality Indicators, Health Care; Natriuretic Peptides; Standard of Care; Atrial Natriuretic Factor
• Other Study ID Numbers: APEX-STROKE CALM-ICH DOMAIN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No