The Study on the Efficacy and Safety of Using Urapidil Alone or in Combination With Esmolol for the Treatment of Acute Hypertensive Intracerebral Hemorrhage: A Prospective, Open-label, Observational, Multicenter Research
Conditions: Hypertensive Intracerebral Hemorrhage
Sponsor: Qianfoshan Hospital

Clinical Research Protocol
Efficacy and safety study of uradil alone or in combination
with esmolol in the treatment of acute hypertensive cerebral
haemorrhage: a prospective, observational, observational
multicentre study
Study Phases:
Investigator-Initiated Clinical Research
Drug Name:
Urapidil Injection, Esmolol Injection
Clinical Research
Institution:
The First Affiliated Hospital of Shandong First Medical University
(Shandong Qianfoshan Hospital)
Version
Number:
V1.6
Version Date:
June 24, 2024
Confidentiality Statement
The information contained in this protocol is confidential and intended solely for the use of clinical
investigators. It must not be disclosed, except as required by applicable laws or regulations. The
copyright of this protocol belongs to Shandong Qianfoshan Hospital. No part of this document may
be reproduced or distributed to any person not involved in this clinical research, except to those who
have signed a confidentiality agreement with Shandong Qianfoshan Hospital.

Principal Investigator's Protocol Signature Page
I will diligently fulfill my duties as an investigator in accordance with the regulations of the
Chinese GCP. I will personally participate in or directly supervise this clinical research. I am
aware of the clinical application and research status of the investigational drug and the
research protocol for this clinical study. I agree to perform the relevant duties in
compliance with Chinese law, Declaration of Helsinki, Chinese GCP, and this research
protocol. Modifications to the protocol will only be made when necessary to protect the
safety, rights, and welfare of the research participants, and only after approval by the Ethics
Committee. I will be responsible for making clinical medical decisions, ensuring that
research participants receive appropriate treatment in a timely manner in the event of
adverse events, and recording and reporting these adverse events in accordance with
national regulations. I guarantee that the data will be recorded truthfully, accurately,
completely, and in a timely manner. I will accept inspections by drug regulatory authorities
to ensure the quality of the clinical research. I pledge to keep the personal information of
research participants and related matters confidential. I agree to prohibit commercial or
economic activities related to this trial. I consent to the publication of the research results. I
will provide a copy of the principal investigator's CV to the Ethics Committee before the
study begins.
Research Institution: The First Affiliated Hospital of Shandong First Medical University
(Shandong Qianfoshan Hospital)

Confidentiality Statement
The information contained in this document is confidential and is the property of The
First Affiliated Hospital of Shandong First Medical University (Shandong Qianfoshan
Hospital). This protocol provides relevant information for the purpose of conducting a
clinical study by The First Affiliated Hospital of Shandong First Medical University
(Shandong Qianfoshan Hospital). Researchers may disclose the contents of this protocol
to trial participants, institutional review boards, ethics committees, or pharmacy and
therapeutics committees for the same purpose, provided that the following conditions
are met. The contents of this protocol shall not be used in other clinical studies or
disclosed to any other individual or organization without prior written permission from
The First Affiliated Hospital of Shandong First Medical University (Shandong Qianfoshan
Hospital). Although this condition does not apply to disclosures required by law or
regulation, researchers must promptly notify The First Affiliated Hospital of Shandong
First Medical University (Shandong Qianfoshan Hospital) of such disclosures.
Additionally, any supplemental information to this protocol is also confidential and the
property of The First Affiliated Hospital of Shandong First Medical University (Shandong
Qianfoshan Hospital). The principles of confidentiality for supplemental information are
the same as those for the contents of the protocol and may only be used for purposes
authorized by The First Affiliated Hospital of Shandong First Medical University
(Shandong Qianfoshan Hospital). Disclosure to any other person without prior written
permission is prohibited. If you possess this protocol without prior authorization, please

contact The First Affiliated Hospital of Shandong First Medical University (Shandong
Qianfoshan Hospital) promptly and return the protocol and all copies to the hospital.
Research Institution: The First Affiliated Hospital of Shandong First Medical University
(Shandong Qianfoshan Hospital)
Principal Investigator's Name / Date:

1
Compliance Statement
This trial will be conducted in accordance with the International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
Good Clinical Practice (GCP) and the National Medical Products Administration (NMPA)
GCP guidelines for clinical research quality management in China.
The investigators, as well as the staff members of the research institutions responsible
for conducting, managing, and supervising the clinical study, must have completed
training on the protection of human research participants and GCP.
The study protocol, informed consent forms, recruitment materials, and all related
documents will be submitted to the Ethics Committee (EC) for review and approval.
Approval of the protocol and informed consent forms must be obtained prior to the
enrollment of any research participants. All protocol amendments must be reviewed and
approved by the EC before implementation. Furthermore, all changes to the informed
consent forms also require EC approval, and it should be determined whether research
participants who have signed previously approved versions of the informed consent
form need to sign the new version again.

2

3
Ethical Statement
1.Compliance with Documents
This trial must be conducted in accordance with the standard operating procedures of each
participating hospital and in compliance with the research protocol. The design of the
research protocol follows the following documents:
(1)"Measures for the Ethical Review of Human Life-Related Medical Research" (2023)
(2)"Measures for the Ethical Review of Biomedical Research Involving Human Beings"
(2016)
(3)WMA's "Declaration of Helsinki" (2013) (Note: Please specify the full title or document
number if known)
(4)CIOMS's "International Ethical Guidelines for Biomedical Research Involving Human
Subjects" (2002)
(5)Ethical Principles of GCP
(6)"Drug Administration Law of the People's Republic of China"
(7)"Good Clinical Practice Guidelines for Drug Clinical Research"
2.Ethics Committee
Prior to the start of the trial, the investigators must submit the research protocol, informed
consent forms, approval documents from relevant authorities, drug inspection reports, and
any advertisements for recruiting research participants to the Ethics Committee or an

4
organization with equivalent authority for review and approval. The written approval
should be submitted by the investigators to The First Affiliated Hospital of Shandong First
Medical University (Shandong Qianfoshan Hospital).
3.Informed Consent Forms
The informed consent forms must be submitted to the relevant Ethics Committee for
approval, and each form must include all relevant content.
Before any potential research participant and/or their guardian participates in any activities
related to the trial, the benefits and risks of the trial must be fully explained to them. After
explaining the basic content of the trial and ensuring that the investigators are confident
that each research participant and/or their guardian understands the purpose of the trial,
each research participant and/or their guardian should be required to sign and date the
informed consent form. The investigators must provide a copy of the signed informed
consent form to the research participant and/or their guardian.

5
Abbreviations
Abbreviations
Full English Names
HICH
Hypertensive intracerebral hemorrhage
HRV
Heart Rate Variability
URA
Urapidil
ANS
Autonomic nervous system
HRS
Heart Rate Variability
ECG
Electrocardiogram
pk
pharmacokinetics
ADR
Adverse drug reaction
CRF
Case report form
CV%
Coefficient of variation
DRQ
Concentrator data ready queue
EC
Ethics committee
GCP
Good clinical practice
h
Hour
IRB
Institutional review board
kg
Kilogram
AE
Adverse event
SAE
Serious adverse event
SAP
Statistical analysis plan
SUSAR
Suspect Severe adverse reaction

6
Abbreviations
Full English Names
TEAE
Treatment-emergent adverse event

7
Protocol Summary
1.Overview
Study Title
A Prospective, Open-Label, Observational Multicenter Study
on the Efficacy and Safety of Urapidil Alone or in Combination
with Esmolol for the Treatment of Acute Hypertensive
Intracerebral Hemorrhage
Version Number
Version 1.6, June 24, 2024
Leading Institution
The First Affiliated Hospital of Shandong First Medical
University (Shandong Qianfoshan Hospital)
Principal
Investigators
Study Type
Investigator-Initiated Clinical Study
Study Design
Observational Study
Study Drugs
Urapidil, Esmolol
Group Allocation
Urapidil Group
Urapidil Combined with Esmolol Group
Route
of
Administration
Intravenous Infusion via Pump
Objectives
The purpose of this study is to explore the optimal blood
pressure
management
strategy
for
patients
with
acute
hypertensive
intracerebral
hemorrhage
through
a
prospective, open-label, observational, multicenter clinical
study. We aim to assess the impact of two different blood

8
pressure control strategies on patient outcomes and provide
scientific
evidence
to
guide
clinicians
in
formulating
reasonable treatment plans.
Sample Size
300 patients in each group, totaling 600 patients
Gender
Both male and female participants are eligible
Interventions
None (observational study)
Duration
of
Treatment
7 days
Follow-up Period
3 months of routine clinical follow-up
Inclusion Criteria
(1) Participants aged 18 to 80 years with acute hypertensive
intracerebral hemorrhage;
(2) Participants with acute cerebral hemorrhage (basal ganglia
hemorrhage < 50ml) confirmed by imaging within 6 hours of
onset;
(3) Participants with systolic blood pressure > 140 mmHg at
admission;
(4) Participants who have signed the informed consent form.
Exclusion Criteria
(1) Participants with cerebral hemorrhage who refuse to have
their disease management information collected and/or who
refuse to undergo follow-up assessments;
(2) Participants with allergies to the study drugs;
(3) Participants with secondary cerebral hemorrhage due to

9
tumors, vascular malformations, aneurysms, trauma,
thrombolytic therapy, or cerebral arteriovenous thrombosis;
(4) Participants undergoing anticoagulant therapy or with
coagulation disorders;
(5) Pregnant women;
(6) Participants with multiple organ failure;
(7) Participants deemed unsuitable for enrollment by the
investigators due to other factors.
Primary Endpoint
The rate of poor outcomes on the modified Rankin Scale
(mRS)
score
at
3
months
after
onset
among
study
participants, to assess whether blood pressure management
with urapidil combined with esmolol benefits the participants
(poor outcome: scores 4-6).
Secondary
Endpoints
Changes in intracerebral hematoma volume among study
participants, Heart rate variability, Time taken for blood
pressure
to
reach
the
target
level
after
administering
antihypertensive drugs, mRS score at discharge, In-hospital
mortality rate, Mortality rate within 3 months of onset,
Adverse
events
during
hospitalization,
Incidence
of
seizures,Relevant complications,Length of hospital stay.

10
2.Study Flowchart
Screening Period
Treatment and Follow-up Period
V0 (Informed Consent)
V1
(Treatment
Period)
V2 (At Discharge)
V3
(1
Month
Follow-up)
V4
(3
Months
Follow-up)
Obtain
signed
informed
consent,
demographic
information,
and
vital
signs,
Record
concomitant
medications
taken
within
the
past
2
weeks,
Measure
height and weight,
Inquire
about
medical
history,
including
past
illnesses
and
treatment
history,
Document
medication
diagnosis,
Assess
Collect
information
on medication
administration
and
concomitant
medications,
Record
the
time
taken
from the start
of medication
administration
to
the
achievement
of
target
blood
pressure,
Re-evaluate
Prognosis
of
Participants
with
Cerebral
Hemorrhage
(assessed
by
the
Modified
Rankin
Scale
(mRS)
Score),
Review
and assessment
of
adverse
events; If routine
laboratory tests
such
as
complete blood
count,
biochemistry
tests
(liver
and
kidney function,
blood
glucose,
blood lipids) are
Prognosis
of
Participants
with
Cerebral
Hemorrhage
(assessed by the
Modified
Rankin
Scale
(mRS)
Score),
Review
and
assessment
of
adverse events;
If
routine
laboratory
tests
such
as
complete
blood
count,
biochemistry
tests (liver and
kidney
function, blood
Prognosis
of
Participants
with
Cerebral
Hemorrhage
(assessed
by
the
Modified
Rankin
Scale
(mRS)
Score),
Review
and assessment
of
adverse
events;
If
routine
laboratory tests
such
as
complete blood
count,
biochemistry
tests (liver and
kidney
function, blood

11
Glasgow Coma Scale
(GCS)
score,
blood
pressure, heart rate,
and
initial
CT
hematoma
size
upon
admission,
Collect
information
related
to
surgical
procedures, if any, If
routine
laboratory
tests
such
as
complete
blood
count, biochemistry
tests
(liver
and
kidney
function,
blood
glucose,
blood
lipids),
procalcitonin,
CRP,
and etiological tests
are
performed
clinically,
gather
relevant information,
intracranial
hematoma
size, heart rate
variability,
monitor blood
pressure,
and
assess
the
incidence
of
seizures
and
related
complications
within
24
hours
of
admission,
Review
and
evaluate
adverse
events, Fill out
the
case
report
form
accordingly.
performed
clinically, gather
relevant
information, Fill
out
the
case
report form.
glucose, blood
lipids)
are
performed
clinically,
gather relevant
information,
Fill out the case
report form.
glucose,
blood
lipids)
are
performed
clinically,
gather relevant
information, Fill
out
the
case
report form.

12
Fill
out
the
case
report
form
and
other
necessary
documents.

13
3.Study Schedule
Protocol
V0
V1
V2
V3
V4
Informed Consent Form X
Demographic
X
Height
X
Weight
X
Medical History
X
Medication Diagnosis
X
Complete
Blood
CountX
X
X
X
Biochemical Examination X
X
X
X
Procalcitonin
X
X
Cranial CT
X
X
X
X
X
Blood
PressureX
X
X
X
X
Heart
Rate
VariabilityX
X
Outcome of Intracerebral
X
X
X
X
Concomitant
MedicationX
X
X
X
X
Adverse Event Review andX
X
X
X
X
Case Report Form (CRF)
X
X
X
X
X
*If there are routine clinical tests, collect them.

14
Main Body of the Proposal
1. Introduction
Hypertensive intracerebral hemorrhage (HICH) is a common and serious condition that
poses significant challenges to the medical community due to its complexity and the
severity of its outcomes. Over the past few decades, there has been considerable debate
regarding blood pressure management strategies for patients with acute hypertensive
intracerebral hemorrhage. Both hypertension and hypotension following intracerebral
hemorrhage are associated with poor outcomes. Several trials aimed at reducing blood
pressure in acute intracerebral hemorrhage patients have demonstrated a correlation
between reduced blood pressure and decreased hematoma expansion in patients recruited
within 6 hours of symptom onset. Current international guidelines, including those from
the European Stroke Organization, the American Heart Association (AHA)/American Stroke
Association, and the Canadian Stroke Best Practice Recommendations, advocate for
lowering systolic blood pressure (SBP) to 140 mmHg as soon as possible after symptom
onset, with a target of maintaining SBP between 130 and 150 mmHg. However, for certain
patients, such as those with extremely high post-ICH blood pressure (SBP > 220 mmHg), a
more individualized approach is necessary. Notably, patients with extremely high blood
pressure (SBP > 220 mmHg) were not included in these trials, and lowering SBP to 140

15
mmHg in this population may be harmful, with an increased incidence of neurological
deterioration and adverse renal events.
Elevated blood pressure (BP) is common in patients with acute spontaneous intracerebral
hemorrhage (ICH) and is closely associated with hematoma growth, a significant
independent predictor of clinical deterioration and outcomes in ICH patients. Previous
studies have shown that hematoma growth predominantly occurs within the first 6 hours
following spontaneous intracerebral hemorrhage. Therefore, early blood pressure
reduction may help prevent hematoma growth. Research has indicated that ICH patients
who achieve target BP sooner after onset are less likely to experience hematoma growth.
Specifically, ICH patients who reach the target SBP of <140 mmHg within the first hour
after randomization exhibit a lower absolute rate of hematoma enlargement. These
findings support the benefit of reducing the time to reach target BP in ICH patients, with
hematoma growth primarily attributed to ongoing bleeding and secondary vascular
rupture. Hematoma growth predominantly occurs within the first 6 hours following ICH
onset, particularly within the initial 2-3 hours, and the frequency of hematoma growth
decreases as time progresses.
Autonomic nervous system (ANS) changes have been observed in patients with acute
stroke, characterized by impaired cardiovascular regulation and a shift in the balance
between sympathetic and parasympathetic activity. Clinically, ANS dysfunction has been
associated with poor prognosis, increased mortality, and sudden death following stroke.

16
Heart rate variability (HRV) and baroreceptor sensitivity (HRS) changes are traditionally
considered surrogate markers of cardiovascular ANS regulation. Previous studies on HRV
in acute brain injury have primarily focused on ischemic stroke or traumatic brain injury
(TBI). In TBI and ischemic stroke, HRV parameters have been shown to be independently
associated with outcomes.
Urapidil (URA) is a selective α1-adrenoceptor antagonist and a central nervous system
5-HT1A receptor agonist, with dual peripheral and central antihypertensive effects. The
antihypertensive effect of URA is dose-dependent and exhibits individual variability. URA
has a self-limiting hypotensive effect, and even at higher doses, severe hypotension does
not occur. URA reduces both pre- and afterload on the heart, decreases myocardial oxygen
consumption, and increases cardiac output without causing reflex tachycardia or affecting
heart rate. Additionally, URA does not increase intracranial pressure or affect cerebral
artery hemodynamics, thereby helping to maintain cerebral perfusion pressure. URA also
increases renal blood flow, reduces renal vascular resistance, and does not increase
pulmonary blood shunt or decrease arterial oxygen partial pressure.
Esmolol is an ultra-short-acting, highly selective β1-adrenoceptor blocker that primarily
antagonizes β1 receptors in myocardial cells. By blocking the activity of adrenaline and
norepinephrine, it exerts its pharmacological effects. At higher doses, it also blocks β2
receptors in bronchial and vascular smooth muscle. Esmolol lacks intrinsic
sympathomimetic activity or membrane-stabilizing effects at therapeutic doses. When

17
administered intravenously, it takes effect within 60 seconds, and its pharmacological
action dissipates within 10-30 minutes after infusion cessation. Electrophysiological studies
suggest that esmolol exhibits typical β1 receptor blockade effects, such as reducing heart
rate, prolonging the sinus cycle, extending sinus node recovery time, and prolonging the
AH interval and anterograde Wenckebach cycle. It also slows conduction in the atrial and
ventricular myocardium and cardiac conduction system, extending the refractory period.
By blocking sympathetic nerve excitation, esmolol lowers the ventricular fibrillation (VF)
threshold.
Participants in studies on acute hypertensive intracerebral hemorrhage often experience
increased heart rates and difficulty in controlling blood pressure. Previous studies have
indicated that the time taken to lower blood pressure to normal levels and heart rate
variability are associated with poor outcomes in study participants. This study aims to
evaluate the efficacy of treatment strategies involving urapidil alone and in combination
with esmolol for blood pressure reduction and heart rate control in participants with acute
intracerebral hemorrhage.
2. Trial Design
2.1 Objectives of the Study
The primary aim of this study is to investigate the efficacy and safety of urapidil
monotherapy versus esmolol combination therapy in managing acute hypertensive

18
intracerebral hemorrhage (HICH) through a prospective, open-label, observational,
multicenter clinical trial. The findings will provide guidance for clinicians in developing
optimal treatment protocols.
2.2 Endpoint Metrics
2.2.1 Primary Endpoint
The primary endpoint is the unfavorable modified Rankin Scale (mRS) score (≥4) at 3
months post-onset, assessing the benefit of blood pressure control with urapidil and
esmolol combination therapy for study participants.
2.2.2 Secondary Endpoints
Changes
in
intracerebral
hematoma
volume
during
the
acute
phase,Heart
rate
variability,Time
to
achieve
target
blood
pressure
after
initiating
antihypertensive
medication,mRS
score
at
discharge,In-hospital
mortality,Mortality
within
3
months
post-onset,Adverse
events
during
hospitalization,Incidence
of
seizures,Related
complications,Length of hospital stay
3. Study Design
3.1 Overall Design
1.This study employs a prospective, open-label, observational, multicenter clinical trial
design. Participating centers must meet the following criteria:
2.Annual admission of over 100 HICH patients.
3.Availability of an intensive care unit (ICU, NICU not mandatory).

19
4.Dedicated
researchers
(with
associate
professor
or
higher
title)
and
research
coordinators/graduate students for the study.
5.Completion of pre-study training by all participating personnel.
6.Agreement to strictly adhere to the study protocol, collect data during hospitalization,
and sign a contractual agreement prior to participant enrollment.
Data collection will occur at the following timepoints: admission, during hospitalization,
pre-discharge, 1 month, and 3 months post-onset. If feasible, follow-ups at 6 and 12
months will be requested with participant consent.
3.2 Participating Centers and Principal Investigators
Lead Center:
The First Affiliated Hospital of Shandong First Medical University (Qianfoshan Hospital of
Shandong Province)
Sub-centers:
Heze Hospital of Shandong Provincial Hospital, Xiajin County People's Hospital, Shanxian
Central Hospital, Caoxian County People's Hospital, Liaocheng Brain Hospital, Liaocheng
Second People's Hospital, Linyi People's Hospital, Shandong Provincial Third Hospital,
Jining First People's Hospital, Affiliated Hospital of Jining Medical University, Pingyin
County People's Hospital, Zhangqiu District People's Hospital, Jinan People's Hospital,
Tai'an Central Hospital, The Second Affiliated Hospital of Shandong First Medical University,
Zibo Central Hospital, Weifang People's Hospital, Affiliated Hospital of Binzhou Medical

20
University, Qingdao Municipal Hospital, Yantai Yuhuangding Hospital, Weihai Municipal
Hospital, Yiyuan Traditional Chinese Medicine Hospital, Ningyang Traditional Chinese
Medicine Hospital, Qingyun County People's Hospital, Dezhou Seventh People's Hospital,
Hantai County People's Hospital, Pingyin County Traditional Chinese Medicine Hospital,
Yiyuan County People's Hospital
3.3 Roles and Responsibilities in a Multicenter Study
Lead Center:
(1).Initiates study planning, designs the protocol and research flow, incorporating feedback
from sub-center PIs to ensure advancement, rationality, and feasibility.
(2).Selects
eligible
sub-centers,
ensuring
rigorous
selection
based
on
regional
representation, number of required centers, and eligibility criteria. Assists in ethics
submission and approval.
(3).Executes designated research tasks per the protocol.
(4).Oversees
quality
control
throughout
the
study,
ensuring
compliance
and
data
authenticity.
(5).Establishes a data platform for timely data uploads and participant confidentiality.
(6).Analyzes and summarizes study results post-completion.
Sub-centers:
(1).Collaborates with the lead center's PI, offering input on the study design.
(2).Submits and obtains ethics approval with the lead center's assistance.

21
(3).Conducts designated research tasks per the protocol, adhering to compliance and data
authenticity.
(4).Accepts oversight and suggestions from the lead center.
(5).Regularly uploads data as required, maintaining participant confidentiality
3.4 Multicenter Training and Quality Control
Prior to the study's commencement, an initial meeting is conducted to provide uniform
training to investigators from all centers, encompassing the study protocol, informed
consent procedures, and case report form (CRF) completion. During the study's
progression, quality controllers from the lead center regularly conduct quality assurance
checks on enrollment progress, medical records, informed consent forms, and CRFs across
centers. Upon study completion, data quality controllers review the data, ensuring its
accuracy and completeness before submitting it to statistical analysts for analysis as per
the study requirements.
3.5 Sample Size Calculation
This study employs a prospective, open-label, observational design, with the primary
endpoint being the unfavorable mRS score (≥4) at 3 months post-treatment. Based on
guidelines [4] and relevant literature [24], we assume a 38% unfavorable mRS rate for the
urapidil and esmolol combination group and a 55% rate for the urapidil monotherapy
group. Using PASS software, with the Tests for Two Proportion module, we calculate the
required sample size with a one-sided α of 0.05, a power of 0.9, and an anticipated

22
dropout rate of 20%. The initial sample size calculation yields 183 participants; however, to
account for potential losses due to propensity score matching (PSM), the final sample size
is determined as 300 participants per group.
3.6 Study Medications and Treatment Protocol
The study medications, urapidil injection and esmolol injection, are routine hospital drugs.
Urapidil Injection (Shijiazhuang No. 4 Pharmaceutical Co., Ltd., National Medical Products
Administration Approval No. H20233626): An initial bolus of 10 mg is administered
intravenously over a slow injection, followed by a 5-minute observation period. The
infusion rate is then adjusted based on the patient's blood pressure, generally not
exceeding 2 mg/min.
Esmolol Injection (Qilu Pharmaceutical Co., Ltd., National Medical Products Administration
Approval No. H19991058): A bolus of 1 mg/kg is administered intravenously within 30
seconds, followed by a maintenance infusion rate adjusted based on blood pressure, not
exceeding 300 μg/kg/min.
3.7 Basic Treatment
Standard basic treatments for cerebral hemorrhage include blood pressure management,
cerebral edema and intracranial pressure control, hemostasis, sedation and analgesia,
respiratory support, maintenance of electrolyte and fluid balance, nutritional support,
prevention of complications (such as deep vein thrombosis, lung infections, pressure
ulcers), and rehabilitation therapy.

23
4. Study Population
The recruitment of participants for this study on hypertensive intracerebral hemorrhage
will be completed between August 2024 and August 2025.
Recruitment Sites:
The First Affiliated Hospital of Shandong First Medical University (Qianfoshan Hospital of
Shandong Province) and its participating sub-centers.
4.1 Inclusion Criteria
Participants eligible for this clinical study must meet all of the following criteria:
(1).Age between 18 and 80 years, with acute hypertensive intracerebral hemorrhage.
(2).Confirmed acute cerebral hemorrhage (basal ganglia hemorrhage < 50 ml) within 6
hours of onset, based on imaging.
(3).Systolic blood pressure > 140 mmHg at admission.
(4).Signed informed consent form.
4.2 Exclusion Criteria
Participants meeting any of the following criteria will be excluded from the study:
(1).Refusal to allow the use of their medical information for research or follow-up.
(2).Allergy to the study medications.
(3).Secondary cerebral hemorrhage due to tumors, vascular malformations, aneurysms,
trauma, thrombolytic therapy, or cerebral venous thrombosis.
(4).Current anticoagulation therapy or impaired coagulation function.

24
(5).Pregnancy.
(6).Multi-organ failure.
(7).Any other factors deemed unsuitable for inclusion by the research team.
5.Study Procedures
Group Allocation: Patients are categorized into two groups based on their actual clinical
medication: the Urapidil group and the combined Urapidil and Esmolol group. Propensity
score matching (PSM) is applied to adjust for confounding factors such as age and gender,
thereby eliminating their potential influence between the two groups. Recruitment and
observation of study participants are conducted by designated research doctors and
nurses within the project team. Each group is further subdivided into two based on the
volume of bleeding (<30ml group, >30ml group).
Treatment Protocol for Abnormal Physiological Indicators: When participants exhibit
abnormal physiological indicators, the treatment team formulates the optimal plan based
on their expertise, guidelines, and the latest literature. The following objectives serve as
guidelines for rapid correction (within 1 hour) and maintenance for 7 days or until early
discharge (or death within 7 days).
(1).Blood Pressure Management: Maintain systolic blood pressure at 130-140mmHg for 7
days using Urapidil or a combination of Urapidil and Esmolol.

25
(2).Intracranial Pressure Reduction: Reduce intracranial pressure through dehydrating
therapies like mannitol, strategic positioning, and if necessary, surgical interventions like
decompressive craniectomy to prevent cerebral hernia.
(3).Temperature Control: Aim for a body temperature of ≤37.5°C.
(4).Anticoagulation
Reversal:
Target
an
INR
level
of
<1.5,
corrected
through
the
administration of Vitamin K, Prothrombin Complex Concentrate (PCC), or Fresh Frozen
Plasma (FFP).
(5).Blood Sugar Regulation: For non-diabetic participants, maintain blood sugar levels at
6.1-7.8mmol/L; for diabetic participants, 7.8-10.0mmol/L.
5.1 Visit V0 (Screening Phase)
Informed Consent: Participants and their families must voluntarily sign a written informed
consent form prior to screening. Only those who meet all inclusion criteria and none of the
exclusion criteria are eligible to participate.
Data Collection: Collect demographic information (age, gender, ethnicity), height, weight,
medical history, medication history (including prior 2 weeks), GCS score at admission,
blood pressure, heart rate, initial CT hematoma size, surgical details, routine laboratory
tests (if available: blood count, liver/kidney function, blood sugar, lipids, procalcitonin, CRP,
pathogens), and fill out the case report form.
5.2 Visit V1 (Treatment Phase)

26
Medication Information: Collect data on antihypertensive and concomitant medications,
time taken to achieve target blood pressure, and 24-hour post-admission CT scan results
for hematoma size.
Heart Rate Variability (HRV) Analysis: Post-target blood pressure achievement, assess
HRV using ECG or telemetry, focusing on R-R intervals. Analyze HRV using time-domain
and frequency-domain methods to quantify cardiac autonomic activity.
Time-Domain Analysis: Includes metrics like average heart rate (AVHR), standard
deviation of NN intervals (SDNN), root mean square of successive differences (RMSSD),
percentage of NN intervals differing by >x ms (pNN20/pNN50), and standard deviation of
the average NN intervals for each segment (SDANN). Values <100ms indicate reduced HRV,
and <50ms significantly reduced, potentially predictive of ventricular arrhythmias.
Frequency-Domain Analysis: Comprises ultra-low, very-low, low, and high-frequency
power components, with low frequency related to baroreflex sensitivity and high frequency
linked to vagal efferent activity.
Blood Pressure Monitoring: Use automated or manual sphygmomanometers with
appropriately sized cuffs on the non-paretic arm. Record blood pressure every 15 minutes
for the first hour, then every 6 hours until 24 hours. Continue this every 6 hours until day 7
or discharge.
Complication
Monitoring:
Record
the
incidence
of
seizures
and
other
related
complications, review and assess adverse events, and update the case report form.

27
5.3 Visit V2 (Discharge)
Assess vital signs, prognosis using the modified Rankin Scale (mRS), medication use,
adverse events, routine laboratory tests, and update the case report form.
5.4 Visit V3 (1-Month Follow-up)
Repeat assessments of vital signs (including height, weight, blood pressure, heart rate),
prognosis (mRS), medication use, adverse events, routine laboratory tests, and update the
case report form.
5.5 Visit V4 (3-Month Follow-up)
Three months after treatment, participants will undergo a follow-up visit encompassing the
following:
Vital signs assessment (height, weight, blood pressure, heart rate);
Prognosis evaluation of cerebral hemorrhage participants using the modified Rankin Scale
(mRS) score;
Collection of medication information;
Review and assessment of adverse events;
Routine laboratory tests, including blood count, liver/kidney function, blood sugar, lipids,
procalcitonin, CRP, and pathogen tests (if applicable), with relevant information recorded;
Completion of the case report form.
6. Biological Sample Collection

28
All routine clinical samples (blood count, liver/kidney function, blood sugar, lipids,
procalcitonin, CRP, pathogen tests, etc.) will be collected by clinical physicians or nurses. To
minimize pain and discomfort, the source of samples will be determined by the medical
team and researchers based on the participants' specific clinical conditions. The sampling
protocol will be tailored by clinical staff according to the participants' individual conditions
and corresponding treatment plans. Sampling timing can be scheduled and adjusted as per
clinical needs.
7. Study Intervention Suspension and Participant Withdrawal/Discontinuation
7.1 Study Intervention Suspension
Should circumstances arise where study members are unable to continue the research,
they must notify the principal investigator and the ethics committee, with reasons stated.
7.2 Participant Withdrawal/Discontinuation from the Study
7.2.1 Criteria for Suspension of Trial:
(1).If the investigator determines that continuing the trial would be detrimental to the
participant.
(2).If the participant expresses unwillingness to continue the clinical study, requests
withdrawal from the study, and withdraws the informed consent.
7.2.2 Criteria for Ending Clinical Study:
(1).Serious safety issues arise during the study, necessitating immediate termination.
(2).The ethics committee requires trial termination following its review.

29
(3).The health administrative department orders the termination of clinical research for any
reason.
(4).The clinical therapeutic effect is found to be inadequate, lacking clinical value.
(5).Significant deviations occur in the study design or implementation, making it difficult to
evaluate the therapeutic effect.
8. Study Evaluation
8.1 Efficacy Assessment
8.1.1 Demographic Data Collection
Includes age, weight, height, and ethnicity.
8.1.2 Efficacy Evaluation
The therapeutic effect is assessed based on the change in mRS scores before and after
treatment.
8.1.3 Other Clinically Significant Changes from Screening
Monitor and record clinically relevant laboratory indicators such as red blood cell count,
hemoglobin, and coagulation during participant follow-ups to assess other significant
changes.
8.2 Safety Assessment
From enrollment to 3 months post-treatment, any adverse reactions experienced by
participants should be promptly recorded.
9. Adverse Events, Serious Adverse Events, and Safety Risk Management

30
9.1 Definition of Adverse Events (AEs)
An AE is defined as any untoward and unintended medical occurrence in a patient or
clinical study participant administered a medicinal product during a clinical study, which
does not necessarily have a causal relationship with the treatment. AEs include clinically
significant abnormalities in laboratory test results that may indicate a disease or organ
dysfunction. All observed AEs or those voluntarily reported by participants should be
recorded in both the source documents and the CRF.
9.1.1 Collection of Adverse Events (AEs)
AEs in clinical studies are collected from the time of the first drug administration to the
participants until three months post-treatment. For each AE, details such as the time of
occurrence, severity, duration, management measures, and outcome must be described.
Furthermore, an assessment of the causal relationship with the study drug and whether it
meets the criteria for a serious adverse event (SAE) is conducted. If an SAE criterion is met,
it must be recorded and reported following the SAE reporting process.
9.1.2 Criteria for Severity of Adverse Events
When completing the AE form, investigators will use the Common Terminology Criteria for
Adverse Events (CTCAE) version 5.0 to evaluate the intensity of AEs. The grading of event
severity is standardized as follows:
Grade 1: Mild; asymptomatic or mild symptoms; only clinical or diagnostic observations;
no treatment required.

31
Grade 2: Moderate; requiring minimal, local, or non-invasive intervention; limitation in
age-appropriate instrumental activities of daily living (e.g., cooking, shopping, using the
telephone, managing finances).
Grade 3: Severe or medically significant but not immediately life-threatening; resulting in
hospitalization or prolongation of hospitalization; disabling; limitation in self-care activities
of daily living (e.g., bathing, dressing, eating, toileting, taking medications), not bedridden.
Grade 4: Life-threatening; requiring urgent intervention.
Grade 5: Death related to the AE.
9.1.3 Criteria for Assessing the Relationship Between Adverse Events and Study Drugs
Investigators must assess the potential association between AEs and the study drug or
concomitant medications using a five-point scale:
(1).Definitely related: The reaction occurs in a reasonable temporal sequence to drug
administration, matches a known reaction type of the suspected drug, resolves upon drug
discontinuation, and cannot be explained by the participant's clinical state or other
reasons.
(2).Probably related: The reaction occurs in a reasonable temporal sequence, matches a
known reaction type, significantly improves upon drug discontinuation, and cannot be
explained by the participant's clinical state or other reasons.

32
(3).Possibly related: The reaction occurs in a reasonable temporal sequence, matches a
known reaction type, may improve upon drug discontinuation, but could also be explained
by the participant's clinical state or other reasons.
(4).Unlikely related: The reaction's temporal sequence or type does not match well with the
suspected drug, does not improve upon drug discontinuation, and could be explained by
the participant's clinical state or other reasons that improve with time or resolution.
(5).Definitely unrelated: The reaction's temporal sequence or type does not match the
suspected drug, and can be explained by the participant's clinical state or other reasons
that improve with time or resolution.
The first three categories are considered adverse reactions to the trial drug, and the
incidence of adverse reactions is calculated accordingly.
9.1.4 Follow-up of Adverse Events
1.Treatment-related AEs of any grade should be followed up until:
(1).Resolution or improvement to baseline levels.
(2).Reassessment of the relationship with the study drug determines it to be unrelated, and
the investigator confirms no further improvement is expected.
2.Treatment-unrelated AEs should be followed up until:
(1).The investigator confirms no further improvement is expected.
(2).The study database is closed, and no further safety data is collected.
3.Outcomes of AEs:

33
(1).Resolved without sequelae: Full recovery from the AE with no lasting effects.
(2).Resolved with sequelae: Recovery from the AE with residual effects.
(3).Not resolved: The AE persists.
(4).Death: The participant dies due to the AE. If possible, an autopsy report should be
attached to the Case Report Form (CRF).
(5).When further information is unlikely to be obtained (e.g., patient or healthcare provider
refuses to provide more information, or evidence suggests maximum efforts have been
made but the patient is lost to follow-up).
Note: The end date and final outcome of all AEs must be recorded in the CRF.
4.Treatment Interventions and Measures Related to the Study Drug:
Any interventions for AEs must be recorded in the concomitant therapy section of the CRF,
specifying whether they are pharmacological or non-pharmacological.
Record measures taken related to the study drug:
(1).None: No measures related to the study drug were taken.
(2).Interrupt/Adjust:
Temporary
discontinuation
of
the
study
drug,
with
possible
re-initiation upon symptom resolution.
(3).Stop: Permanent discontinuation of the study drug.
9.2 Definition of Serious Adverse Events (SAEs)
Serious Adverse Event (SAE): An adverse event that meets any of the following criteria:
(1).Results in death of the study participant.

34
(2).Is life-threatening to the study participant.
(3).Requires hospitalization or prolongation of existing hospitalization.
(4).Results in persistent or significant disability/incapacity.
(5).Constitutes a congenital anomaly/birth defect, or is a medical event deemed serious by
the investigator.
All SAEs occurring during clinical research must be documented in SAE reporting forms.
9.2.1 Reporting of SAEs
The investigator must complete an SAE report form whenever a study drug-related SAE
occurs.
9.2.2 Follow-up of SAEs
1.For SAEs unrelated to treatment: Follow-up should continue until:
(1).Resolution or improvement to baseline levels.
(2).The investigator confirms no further improvement or stability of the SAE.
2.For SAEs related to treatment: Follow-up should continue until:
(1).Resolution or improvement to baseline levels.
(2).The investigator confirms no further improvement or stability of the SAE.
9.2.3 Investigator's Responsibilities in SAE Management
1.Implement necessary and reasonable medical measures to ensure the safety of study
participants.
2.Determine the relevance of the SAE to the trial or trial medication.

35
3.Maintain accurate records and follow-up of SAEs.
4.Report promptly to relevant authorities as required by GCP.
9.3 Definition of Significant Medical Events
Significant medical events are those that, based on appropriate medical and scientific
judgment, may not immediately threaten life or result in death or hospitalization but have
the potential to harm study participants or require intervention (e.g., medical or surgical) to
prevent an SAE.
9.4 Definition of Adverse Reactions (ARs)
Adverse Reaction (AR): A harmful and unintended response to a medicinal product
occurring at doses normally used for the prophylaxis, diagnosis, or treatment of a disease,
or a manifestation of such a response. It excludes reactions caused by drug abuse,
overdose, misuse, or quality issues.
9.5 Suspected Unexpected Serious Adverse Reactions (SUSARs)
All SAEs are subject to review by clinicians. For each death case, a determination must be
made whether it is natural or caused by drug-related/non-drug-related SAEs. Drug-related
SAEs not included in the trial protocol or product characteristic summary are classified as
SUSARs.
9.6 Emergency Response Plan for Cerebral Hemorrhage
(1).Immediate Assessment: The medical team conducts a rapid assessment, including vital
signs, neurological signs, and imaging studies (e.g., CT scan if necessary).

36
(2).Stabilization: Measures are taken to stabilize vital signs, ensure airway patency,
administer oxygen therapy or mechanical ventilation, and maintain blood pressure and
circulation through intravenous fluids.
(3).Emergency
Surgery:
If
significant
cerebral
hemorrhage
or
severe
intracranial
hypertension
occurs,
immediate
assessment
for
neurosurgical
intervention
(e.g.,
hematoma evacuation, decompressive craniectomy) is conducted.
(4).Postoperative Monitoring: Patients are transferred to the Intensive Care Unit (ICU) for
close monitoring and symptomatic treatment.
Section 10. Statistical Methods
10.1 Analysis Sets
(1).Safety Analysis Set (SS): Includes all study participants who were enrolled, received the
study drug, and had safety data recorded.
(2).Efficacy Analysis Set (ES): Comprises all study participants who were enrolled, received
the study drug, and had pre- and post-treatment efficacy evaluation data.
10.2 General Analysis
Data analysis is performed using SPSS 26.0. Continuous data are summarized using mean,
standard deviation, median, minimum, and maximum values. Categorical data are
summarized using frequencies and percentages.
(1).For normally distributed continuous variables, the t-test is used to compare groups.
(2).For non-normally distributed variables, the Mann-Whitney U test is applied.

37
(3).For categorical outcomes, Chi-square or Fisher's exact test is used.
(4).A one-sided α of 0.05 is adopted.
(5).Repeated measures are analyzed using repeated measures ANOVA or generalized
estimating equations.
(6).Missing or illogical data can be deleted from analysis.
10.3 Safety Analysis
Safety parameters are summarized and analyzed based on the SS. Adverse events are
coded using MedDRA, and summarized by System Organ Class (SOC) and Preferred Term
(PT), including incidence rates, drug-related event rates, and SAE rates.
10.4 Efficacy Analysis
The summary and analysis of efficacy parameters will be based on the Efficacy Analysis Set
(ES).
11. Data Management
11.1 Data Recording
This study will utilize Case Report Forms (CRFs) for timely, accurate, and complete data
collection and management.
11.2 CRF Completion and Modification
(1).Completion: CRF data originates from source documents such as original records and
laboratory test reports, and must be consistent with these documents. All observations and

38
test results specified in the trial protocol must be recorded in the CRF promptly, accurately,
completely, clearly, and truthfully, without unauthorized alterations.
(2).Modification: If necessary, corrections to CRF data must be made in accordance with
system prompts, detailing the reason for the modification. The EDC system's logical
verification
process
will
check
the
entered
data
for
logical
consistency
and
flag
questionable data for review or explanation by the Principal Investigator (PI) or data entry
personnel.
11.3 Data Entry
Investigators or dedicated data entry personnel will enter data into a computer system for
storage as per the protocol requirements. Data entry personnel will perform checks for
completeness and logical consistency of the entered clinical research data.
11.4 Data Cleaning
Quality control personnel will review the data. A final quality control check will be
conducted by sampling a portion of the database data. The data quality in the database is
considered acceptable if the error rate falls below the specified threshold.
11.5 Data Processing
After data inspection and cleaning, the data will be submitted to statistical analysts for
analysis as required.
11.6 Retention of Study Records
In accordance with GCP principles, investigators must retain all detailed source documents

39
of study participants and record relevant information in the CRF regarding trial progress,
medication administration, laboratory test data, safety data, and efficacy assessments.
Recorded data must be complete, timely, and clear. Source documents, medical records,
etc., should be clear, detailed, and easily identifiable by personnel involved in the clinical
study.
11.7 Use of Stored Samples and Data
Data collected during this clinical study will be analyzed and stored by the project leader.
Obtaining permission from the project leader to transmit data will be part of the informed
consent process. With the consent of the study participant's guardian and approval from
the local institutional ethics review committee, biological samples without personal
identifiers will be stored with the project leader for the same purposes as the collected data.
While maintaining the anonymity of study participant information, code-linked
information between stored biological samples and phenotypic data of their source study
participants will be provided to the project leader. During the study, study participants may
withdraw their informed consent for the storage of their biological samples for other
research, but the informed consent for the storage of biological samples cannot be
withdrawn after the study's completion.
If the project leader, investigators, or medical institutions intend to publish literature or
papers related to this study, they must obtain the consent of the other two parties before
publication.

40
12. Supporting Documents and Operational Considerations
12.1 Regulatory Basis
This clinical study must comply with Good Clinical Practice (GCP), the International Council
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good
Clinical Practice (ICH-GCP), and applicable laws, regulations, and ethical review opinions
within the territory of the People's Republic of China.
12.2 Ethics
12.2.1 Ethics Committee Review
The conduct of this trial follows GCP, relevant regulations, and ethical review opinions.
Before the trial commences, investigators must submit the trial protocol, informed consent
form, study participant recruitment procedures, and other written materials to the ethics
committee for review and approval. The project leader can only proceed with the clinical
study after receiving the ethics committee's approval. During the trial, any new
amendments to the trial protocol, informed consent form, etc., must be reviewed and
approved in writing again as per regulations. The completion or early termination of the
clinical study must also be reported to the ethics committee.
12.2.2 Informed Consent
Before a study participant enrolls in the clinical study, the investigator or their designated
representative will explain the study background, pharmacological characteristics of the
investigational product, trial protocol, potential benefits and risks (including known and

41
foreseeable risks and possible adverse events) to each study participant or their legal
guardian. The legal guardian and the study physician must sign and date the informed
consent form before the study participant enters the trial (before screening exams).
12.2.3 Confidentiality of Study Participants
The collection and collation of data from study participants involved in this clinical research
are limited to the investigation of the pharmacokinetics, tolerability, short-term safety, and
usage of the drug. Adequate measures will be taken during the collection and processing
of these data to ensure confidentiality and compliance with existing laws and regulations
on privacy protection. It is the researcher's responsibility to maintain the anonymity of
study participants. Study participants can only be identified in CRFs or other documents
using uppercase letters, numbers, and/or codes, not their names. Researchers must record
participant codes, names, and home addresses but must keep documents revealing
participant identities strictly confidential.
12.3 Study Termination
12.3.1 Investigator-Initiated Trial Termination
The investigator may request to discontinue the trial due to certain circumstances. The
investigator must notify study participants, the project leader, and the ethics committee of
the termination and provide justification.

42
12.3.2 Project Leader-Initiated Trial Termination
Reasons for the project leader to request trial termination or suspension at a particular site
may include, but are not limited to:
(1).Financial reasons
Administrative reasons
(2).Failure of the investigator to follow the protocol, GCP, etc.
(3).Inability of the investigator to recruit sufficient study participants
(4).Safety concerns
The project leader must notify investigators and the ethics committee in writing and
provide justification before terminating the clinical study.
12.4 Quality Control and Assurance
To ensure the quality of the trial, the project leader (First Affiliated Hospital of Shandong
First Medical University) and key project researchers will develop the clinical study protocol,
relevant contingency plans, and SOPs before the official start of the trial. Relevant
researchers participating in the trial will undergo training related to drug clinical research.
13. Confidentiality and Privacy
Researchers, medical institutions, and their personnel must maintain strict confidentiality
of any information/data related to the clinical study provided by the project leader and any
knowledge/data obtained by medical institutions during the conduct of the clinical study.
Without the written permission of the project leader, no research materials or data can be

43
disclosed to unauthorized third parties. Study participant contact information will be
securely stored at each clinical research center for internal use during the study period.
14. Publication of Research Outcomes
It is planned to publish 1-4 academic papers based on the findings of this study.