Multicenter Randomized Controlled Trial of Vitamin K1 in the Treatment of Spontaneous Intracerebral Hemorrhage
Phase: EARLY_PHASE1
Conditions: Intracerebral Haemorrhage in Cerebellum
Sponsor: HUANG XIANJIAN

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Multicenter randomized controlled trial of vitamin K1 
in the treatment of spontaneous intracerebral 
hemorrhage 
 
1 Background 
1.1 spontaneous intracerebral hemorrhage 
1.1.1 Epidemiological of cerebral hemorrhage 
Cerebral hemorrhage is a kind of acute onset, rapid change, serious disease, which 
accounts for about 10%-25% of cerebrovascular disease, disability rate and fatality rate 
were 70%-80%, 38%-43%, the recurrence rate was about 1 1.8%-11%. Hypertension 
and amyloid cerebrovascular disease are the main causes of primary spontaneous 
intracerebral hemorrhage, and hypertension is the most common risk factor for 
intracerebral hemorrhage. Cerebral hemorrhage not only has a serious impact on 
patients, but also brings heavy burden to society and family. The treatment of cerebral 
hemorrhage is complicated , which is one of the stroke which is proved by evidence-
based medicine to be effective. Standardized treatment and effective integrated 
management can significantly reduce the fatality rate and improve the outcome of 
intracerebral hemorrhage. 
Delayed cerebral hemorrhage is one of the important reasons for the aggravation 
of cerebral hemorrhage . The amount of hematoma in patients with intracerebral 
hemorrhage is closely related to the secondary injury of nerve function, which directly 
affects the prognosis of patients. Delayed cerebral hemorrhage is closely related to 
coagulation dysfunction. The prevention of delayed hemorrhage is an important part in 
the treatment of cerebral hemorrhage. The blood coagulation is initiated immediately 
after Acute intracerebral hemorrhage, and the coagulation process is divided into three 
stages: prothrombin complex formation, prothrombin activation, and fibrin formation. 
Synthesis of Coagulation factor FX, F II, F VII and F IX are dependent on vitamin K1. 
Vitamin K1 can cause the formation of prothrombin complex, clot solid, effectively 
blocking the vascular rupture, so that the amount of bleeding decreased. However, 

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while controlling bleeding, the risk of thrombosis may be induced, and how to 
effectively control bleeding and avoid thrombosis is often a clinical problem. 
1.2 Introduction of vitamin K1 injections 
Vitamin K1 is an essential substance in the synthesis of prothrombin in the 
liver and can cause coagulation disorders when lacking. When the lack of prothrombin 
in the blood, blood coagulation will appear slow, then add appropriate amount of 
vitamin K1 can promote liver synthesis of prothrombin, play a role in hemostasis. 
Vitamin K1 as pharmaceutical formulations, applied to low thrombin disease, vitamin 
K1 deficiency，the prevention and treatment of neonatal hemorrhage，obstructive 
jaundice, biliary fistula, chronic diarrhea in clinic, Hypoprothrombinemia caused by 
coumarin and sodium salicylate etc.. Vitamin also has the effect of relieving pain and 
relieving bronchospasm, and has obvious effect on colic caused by visceral smooth 
muscle, colic, spasm of bile duct and spasm of intestine. Vitamin K1 can also be used 
as an additive for multidimensional foods and livestock feed. 
Vitamin K1 indications: 1, low blood coagulation: intramuscular or deep subcutaneous 
injection, each time 10mg, 1-2 times a day, within 24 hours the total amount of not more 
than 40mg. 2, prevention of neonatal hemorrhage: 12-24 hours before delivery, 
intramuscular injection or slow intravenous injection 2 - 5mg. 0.5-1mg can also be 
injected intramuscularly or subcutaneously after birth, and can be repeated after 8 hours. 
3, this product is used in patients with severe static injection, the speed of medication 
should not exceed 1mg/. 4, can be used for chronic poisoning caused by brodifacoum. 
Specific usage: (1) intravenous injection of 5 mg / kg vitamin K1, such as the need to 
repeat 2-3 times, each time interval of 8-12 hours. (2) oral administration of 5 mg / kg 
of vitamin K1 for 10-15 days. (3) intravenous injecting 200 ml of lemon acidified blood. 
1.3 Possible risks 
Adverse reactions of vitamin K1: occasionally allergic reactions. Mainly 
occurs when the intravenous injection is too fast, more than 5mg/ minutes 
can cause facial flushing, sweating, bronchospasm, tachycardia, 

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hypotension, etc., serious allergic reactions may endanger life. 
Intramuscular injection can cause redness and swelling. The newborn may 
suffer from hyperbilirubinemia, jaundice and hemolytic anemia after the 
use of the product. 
.1.4. Benefits 
Cerebral hemorrhage is a common disease in Department of 
neurosurgery. It is an important measure to reduce the mortality and 
disability rate in the acute stage. Vitamin K1 may reduce the risk of 
rebleeding in patients with intracerebral hemorrhage, and the amount of 
brain bleeding is directly related to prognosis. Effectively reduce the 
amount of intracerebral hemorrhage, improve the prognosis, reduce the 
length of stay, reduce the time of admission to ICU and reduce the mortality. 
2 Test purpose 
The effectiveness and safety of vitamin K1 were mainly targeted at 
patients with cerebral hemorrhage (non aneurysm or vascular 
malformations, rupture, bleeding). To observe whether vitamin K1 can 
effectively avoid the increase of cerebral hemorrhage and improve the 
prognosis. 
3 Test design 
The study included spontaneous hypertensive intracerebral 
hemorrhage at super tentorium of cerebellum  patients as the research 
object, to exclude cerebral aneurysms or cerebral hemorrhage, venous 

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malformation of abnormal liver function, taking anticoagulants or 
antiplatelet drugs in patients. The study was divided into the experimental 
group and the control group, and a multicenter randomized controlled trial 
was conducted. In the use of a etamsylate intravenous infusion of 0.5g of 
patients admitted to hospital within 8 hours later, the experimental group 
in the incidence of cerebral hemorrhage within 2 days after the daily 
intravenous infusion of vitamin K1 20mg, the control group received 
intravenous saline, all patients were no longer use other hemostatic agents. 
The efficacy and safety of vitamin K1 in the early onset of cerebral 
hemorrhage were assessed by the observation between two groups. 
A randomized, single blind, positive / placebo parallel control, multicenter, 
clinical trial design was used. The treatment lasted for 2 days and followed 
up for 6 months. 
4 Subjects recruited and exited 
4.1 Diagnostic criteria 
4.1.1 Diagnosis of cerebral hemorrhage 
Referring to “Surgery”edited by Chen Xiaoping, and published in 2011 
by people's Medical Publishing house. 
4.1.2 Treatment methods 
According to “Neurosurgery of Wang Zhongcheng”,conventional cerebral 
hemorrhage treatment. 
4.2 Inclusion criteria 

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1）Patients with spontaneous intracerebral hemorrhage (enhanced by cerebral arterial 
CT or cerebral angiography confirmed rupture of non aneurysm or arteriovenous 
malformation); 
3）Age 18-65 years, male or not pregnant female； 
4）GCS score at admission； 
5
）
Head 
CT 
or 
MRI 
examination 
confirmed 
cerebral 
hemorrhage 
at super tentorium of cerebellum and the amount of bleeding in 10ml-45ml (Duotian 
formula to calculate the hemorrhage volume)； 
6）During the hospitalization, no urokinase and other hemostatic drugs were used except 
for the use of K1 and vitamin D in the project； 
7）Informed consent form signed by the patient's family. 
4.3 Exclusion criteria 
1）CT scan and irregular lobulated hematoma, such as intraventricular hemorrhage 
(because no accurate measurement of bleeding)； 
2）Severe liver disease or impaired liver function； 
3）Pregnant or lactating women； 
4）The usage of anticoagulation or antiplatelet aggregation drug history (including 
cilostazol, aspirin, dipyridamole, heparin, low molecular weight heparin, hirudin, 
dabigatran, rivaroxabanand warfarin )； 
5）Non informed consent. 
4.4 Rejection standard 
1）The subjects failed to meet the inclusion criteria and were mistakenly included in 
the trial. 
2）The subjects met either of the exclusion criteria. 
3）No record of any further visits. 
4.5 Exit test standard 
4.5.1 The researchers decided to quit 
1）During the clinical trial, the subjects experienced other complications, complications, 

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or special physiological changes, and were not allowed to continue the experiment.. 
2）Serious adverse events and important adverse events, it is not 
appropriate to continue to accept the test. 
3）The subjects had poor compliance. 
4）The test process meets the rejection criteria. 
4.5.2 The subjects pulled out of their own accord 
1）The subjects were unwilling or unable to continue clinical trials 
and asked the researchers for an exit test. 
2）The subjects were not explicitly asked to quit the trial, but those 
who were not receiving the medication and the test were lost. 
4.5.3 Withdrawal case management 
In the case of the withdrawal from the trial, the researchers should actively take 
measures to complete the final examination as soon as possible to analyze the efficacy 
and safety. All trial cases should be completed in the case report form and the reasons 
for the withdrawal. 
 
5 Suspension test standard 
The discontinuation test means that the clinical trials have not been 
completed by the end of the program. The purpose of the suspension test is 
to protect the rights and interests of the subjects, to ensure the quality of 
the test and to avoid unnecessary economic losses. Standard for 
discontinuation of a test: 
1) serious safety problems in the test, should promptly stop the test. 
2）The trial found that the drug did not have clinical value and should discontinue trials, 
on the one hand, to avoid delaying the effective treatment of the subjects while avoiding 
unnecessary economic losses. 
3）In the experiment, it was found that the clinical trial program had major errors and 

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it was difficult to evaluate the effect of the drug; or a well-designed design, which made 
important deviations in the implementation, and continued, it is difficult to evaluate the 
effect of the drug. 
4）The applicant asked for a suspension (such as funding reasons, management reasons, 
etc.). 
 
6 Treatment Plans 
6.1 Experimental medication 
6.1.1 Drug delivery 
Test drug: vitamin K1 for injection, specification: 10mg each 
Contrast drug: normal saline. 
All trials were administered by the investigators in a single blind manner,. 
6.1.2 Drug storage and stability 
Test drug storage conditions: shading, airtight, cool and dry place to preserve. 
6.1.3 Preparation 
The study nurse assigned the experimental drug according to the instruction 
manual in the kit. Before using, add the test medicine to 100ml 0.9% Sodium Chloride 
Injection and shake it well. 
6.1.4 Route of administration 
Basic treatment: all subjects according to the routine treatment of cerebral 
hemorrhage, the use of Phenol ethylamine intravenous 0.5g within 8 hours after 
admission, another program in accordance with the " Neurosurgery of Wang 
Zhongcheng", including the surgical removal of hematoma and drainage, conservative 
treatment, control of intracranial pressure, prevention of complications. 
Test group： 
Normal saline 100ml+Vitamin K1 20mg，Once a day, intravenous drip, two days in 

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hospital. 
Control group： 
Normal saline 102ml，Once a day, intravenous drip, two days in hospital. 
6.1.5 Test cycle 
Medication for 2 days + followed up for 6 months. 
7 Test procedure and plan 
7.1 Test program evaluation 
①Demographic data: age, sex, and ethnic group. 
②History: ask for or collect current and past medical history based on existing medical 
records. 
③Medication history: before taking the test, take the prescription or over-the-counter 
drugs, and record the generic name, daily total dose, usage and cause of use of the drug. 
④The diagnosis of disease was confirmed by CT or MRI, and the amount of cerebral 
hemorrhage was calculated at the later stage (after the onset of the disease, the 
examination was not repeated). 
⑤Physical examination: vital signs include body temperature (Ye Wen), respiration, 
heart rate, and blood pressure. 
⑥Assessment of biological specimen collection and laboratory: collected blood and 
urine of Hematology, serum biochemistry, pregnancy test and laboratory examination, 
biological specimens from all participating units of the laboratory is responsible for 
collecting, processing, preservation and detection。Prior to the signing of the test drug, 
the clinical trial participant shall provide the bid with the normal reference range of the 
laboratory indicators. If there is any change during the test period, the applicant shall 
be promptly informed of the bid. 
⑦Scale evaluation: mRS score. 
7.2 Test procedure 
Subject to any test procedure, the subjects, legal agents and / or subjects must have 
read and signed an informed consent letter approved by the ethics committee. The test 

9 
 
procedure shall be carried out within the prescribed time window of the visit, as detailed 
in the test flow chart. 

10 
 
 
7.3 Follow-up visit 

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1 months (+ 3 days) and 6 months (= 3 days) after the onset of intracerebral 
hemorrhage: the researchers performed a mRS score using telephone follow-up. 
7.4 Unscheduled visit 
During the trial, unplanned visits should be made if the subject is unwell. 
7.5 Test flow chart 
Time point 
(D0) 
treatment 
vist 
D1 
D3 
D7 
Discharge 
or death 
The first 
month 
The six 
month 
Collect basic information 
informed consent 
√ 
 
 
 
 
 
 
Inclusion Criteria 
√ 
 
 
 
 
 
 
History 
acquisition 
√ 
 
 
 
 
 
 
General 
information  
√ 
 
 
 
 
 
 
Check item 
temperature 
√ 
√ 
√ 
√ 
 
 
 
Vital signs 
√ 
√ 
√ 
√ 
 
 
 
Cerebral 
hemorrhage 
volume（CT） 
√ 
√ 
√ 
√ 
√ 
 
 
 
GCS 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Drugs 
and 
dosages 
√ 
√ 
√ 
 
 
 
 
 
24h intake and 
output 
√ 
√ 
√ 
√ 
 
 
 
Blood 
routine, 
liver and kidney 
function, 
electrolyte 
√ 
√ 
√ 
√ 
√ 
 
 
Platelet  
√ 
√ 
√ 
√ 
√ 
 
 
Coagulation 
function 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Complications 
and 
adverse 
reactions 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
MRS 
 
 
 
 
 
√ 
√ 
 
ICU 
total 
 
 
 
 
√ 
 
 
 

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7.5 Concomitant medication and treatment 
7.5.1 Basic treatment 
Allow the cerebral hemorrhage treated with conventional therapy control of 
intracranial hypertension, prevention of complications, but it must be the case report 
form to record the medicine general or other treatment, dosage, reason, use frequency 
and time etc, so as to summarize, analyze and report. 
7.5.2 No medication or treatment 
During the period of medication and during the follow-up period, drugs that 
affect the efficacy of the regimen may not be used, such as antithrombotic or 
anticoagulant or hemostatic drugs. 
7.5.3 Medication and treatment are permitted 
①The other combined diseases without affecting the curative effect and safety 
evaluation, can be symptomatic medication, but it must be the case report form to record 
the medicine general or other treatment, dosage, reason, use frequency and time etc, so 
as to summarize, analyze and report. 
②The follow-up period can use cognitive rehabilitation methods, including 
occupational therapy, implicit memory rehabilitation, errorless learning, cognitive 
neuropsychological rehabilitation, rehabilitation and computer assisted cognitive 
rehabilitation, virtual remote control via the Internet, and the electromagnetic 
stimulation, should be recorded in detail in CRF. 
③The combination drugs used for adverse events during the trial should be recorded 
in CRF. 
 
8 Therapeutic evaluation standard  
Main outcome measures: the amount of intracerebral hemorrhage (0d, 1D, 3D, 7D) 
at each time after the onset of disease. 
hospital stay 

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Main outcome measures: (1) the amount of the time changes in blood coagulation, 
platelet levels and GCS scores after the onset (0d, 1D, 3D, 7D); (2) days in ICU; (3) the 
total hospitalization days; (4) complications including neurological complications, 
complications, complications, blood coagulation circulatory complications after 
cerebral hemorrhage; (5) 1m and 6m mRS score. 
 
9 Safety evaluation 
9.1 Definition 
Adverse events (Adverse, Event, AE): refers to the patient or clinical trial subjects 
after receiving a drug adverse medical events, but not necessarily have a causal 
relationship with the treatment. 
Serious adverse events (Serious Adverse, Event, SAE): the need for 
hospitalization, prolonged hospitalization, disability, affecting work ability, 
endanger life or death, resulting in congenital malformation occurred 
during the clinical trial. 
Important adverse events are any adverse events or laboratory 
abnormalities that result from the use of targeted medical measures (such 
as discontinuation, dosage reduction, and / or symptomatic treatment) other 
than SAE. 
Adverse drug reactions (ADR): adverse reactions that occur when 
prescribed drugs are applied at prescribed doses, not as desired, but are 
causally related to the use of the drug. In a clinical trial of a new drug or a 
new drug, when the dose of treatment has not yet been determined, all 
harmful reactions that are not expected to cause a causal relationship with 

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the use of the drug should be considered adverse drug reactions. 
9.2 Background data on safety associated with experimental drugs 
The clinical adverse reactions include anxiety, skin itching, rash, 
nausea and stomachache, which can subside spontaneously after 
withdrawal. A small number of patients developed mental excitement and 
abnormal sleep. 
9.3 Handling and recording of adverse events 
9.3.1 Treatment for adverse events 
Inpatient 
If the subject has adverse events during hospitalization, follow the following 
procedures: 
Found adverse events in subjects, tube bed doctor or the doctor on duty shall 
promptly inform researchers, if necessary, can be the first symptomatic treatment, the 
degree of correlation between classification by research physician preliminary 
assessment of adverse events and drug test, and give further advice: 
①  General adverse events: can closely observe the outcome of the event or the 
corresponding symptomatic treatment; 
② Important adverse events: physicians should promptly inform major 
researchers, and pause treatment, adjust drug dosage and targeted treatment 
according to the subjects' condition; 
③ Serious adverse events: follow  "9.4" for processing and reporting. 
④ According to the patient's treatment, if the subject's injury exceeds the capacity 
of the research department, the relevant department should be invited to 
consult and assist in the treatment. 
Outpatient 
The adverse events that the subjects after the study, physicians should ask detailed 
subjects at the time of the symptoms and signs and place, the necessary explanation and 

15 
 
guidance on the subjects, and the degree of correlation of adverse events and give 
preliminary evaluation; as the subjects in the local medical institutions, contact by 
telephone and reception the doctor, check again the degree of adverse events and give 
treatment advice: 
①  General adverse events: initial visit to local hospital and notification of outcome 
of close observation; 
② Important adverse events: recommend returning to the hospital for treatment or to 
the local hospital for treatment, and timely notification of the main researchers, such as 
limited local hospitals, doctors should be sent to the treatment. An emergency envelope 
is also provided for emergency blind use (if applicable). According to the plan request, 
adopts the pause treatment, adjusts the medicine dosage and the symptomatic treatment 
and so on. 
9.3.2 Record of adverse events 
①A physician should perform a record of adverse events, including at least the 
description of the adverse events, the time of occurrence, the length of the termination, 
the frequency of attack, and the need for treatment and, if necessary, records of the 
treatment given. 
② In the original record as far as possible with the occurrence and development of 
SAE records, after the treatment, and record in the CRF table, the SAE track, until we 
get a proper solution or stable disease or a clear reason to research, clinical drug 
research institutions ethics committee, unit state food and drug administration, etc. 
provide a final report. 
9.4 Severe adverse events 
9.4.1 Treatment of severe adverse events 
①In case of SAE, the first visit doctor shall notify the principal investigator or other 
doctors to be present. If  it  is serious, he or she shall notify the project leader when 
subjects are in danger； 
②  As for the judgment of SAE, according to the clinical manifestations , professional 
standard and immediate treatment or rescue measures must be taken; if serious 

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toxicity caused by drug overdose, the researchers decided to accelerate the excretion 
of drugs and take other rescue measures, try to maintain the vital signs of the 
patients to be as stable as possible, ECG monitoring is necessary, if necessary the 
first visit doctor can get help from the relevant departments.   
③ Outside the hospital subjects were judged as SAE and can't come back, they were 
advised to timely return to hospital or go to the local hospital.The researchers should 
immediately notice the person in charge of the project for further treatment; as in the 
local hospital, made contact with the doctors, to understand the specific situation, 
treatment advice. 
9.4.2 Severe adverse events are reported 
Researchers should give immediate rescue to serious adverse events occurred in 
the test , whether or not it is related to the study drug.The researchers should report to 
the relevant provinces, autonomous regions and municipalities directly under the drug 
supervision and administration department and the State Food and Drug Administration 
in 24 hours, report to  the applicant, and ethics committee.  The sponsor and 
researchers should quickly study what happened, and try to take the necessary measures 
to ensure the safety and interests of subjects and report promptly to  administrative 
departments of health and other researchers  involving the same drug. If serious 
adverse events associated with an experimental drug, the Applicant should undertakes 
the costs of the rescue and treatment of the patient and the corresponding financial 
compensation.. The researchers must fill out a "severe adverse event report" which 
should record when, how, and who are reported. The bidder guarantees to meet all legal 
requirements.  
9.4.3 Hospitalization 
Adverse events leading to hospitalization or prolonged hospitalization in clinical 
trials should be considered as serious adverse events. Any first hospitalized (even 
shorter than 24 hours).  Is according to comply with this standard.. 
Hospitalization does not include the following circumstances: 
 Rehabilitation facility 

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 Nursing home 
 Routine routine emergency room admission 
 O day surgery (e.g. outpatient / day / ambulatory surgery) 
Hospitalization or prolonged hospital stays unrelated to worsening adverse events 
are not, in themselves, serious adverse events, for example: 
 Because of the original disease, there is no new adverse event, and there is no 
exacerbation of the original disease. 
 Management for reasons of hospitalization (e.g. routine annual examination). 
 Clinical setting during the clinical trial (for example, according to the 
requirements of the test program). 
 elective hospitalization with adverse events worsening (e.g., elective cosmetic 
surgery). 
 scheduled treatment or surgery should be performed throughout the trial 
program. 
 admission only because of blood use. 
9.5 Grading of adverse events 
Mild: mild symptoms can be tolerated, does not affect activities of daily 
living, symptoms are transient, in the continuing use of drugs during their 
own relief, without treatment. 
Moderate: the symptoms are obvious, affecting the daily activities of the 
subjects, the symptoms for a long time, can be relieved or symptomatic 
relief after treatment. It may interfere with the use of investigational drugs, 
such as reducing drug dosages or stopping medications. 
Severe: the subjects suffered from impaired body function, lost normal 
work and living ability, and had a long duration of symptoms. They had to 
be stopped and properly treated before they could be relieved 

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9.6 Adverse events and test drug evaluation 
According to the sequence between the occurrences of adverse drug evens and 
usage of drugs , the type of drug reaction after drug withdrawal reaction is reduced, will 
disappear or reappear, causality assessment of adverse events related to study drug is 
certainly relevant, probably, may be related, and certainly can not. The first three were 
considered to be relevant to the study of the drug, which was evaluated as  untoward 
effect  of drug .(ADR). 
Adverse events associated with the study of drugs are as follows: 
①Affirmation: the use of evidence for the study of drugs, the occurrence 
of adverse events and research, the use of drugs have a reasonable 
chronological order, adverse events to study drug interpretation, more 
reasonable than other explanations. The drug withdrawal reaction is 
positive, and the repeated use (if feasible) is positive. 
②Likely related: evidence of the use of research drugs, occurrence of 
adverse events, and rational timing of drug use in the study. Adverse events 
are more reasonable in explaining drug explanations than in other 
explanations. Positive drug withdrawal reaction. 
It may be related to the evidence of the use of research drugs, the 
occurrence and use of adverse events, and the timing of the study of drugs. 
Adverse events can also be explained by other reasons. Positive drug 
withdrawal reaction. 
③ Perhaps irrelevant: the use of evidence for the study of drugs, the 
occurrence of adverse events, explained by other reasons is more 
reasonable. Withdrawal reactions were negative or unclear. 

19 
 
④Absolutely unrelated: no use of research drugs, or the use of research 
drugs and adverse events unrelated to the time, or otherwise clearly lead to 
adverse events. 
9.7 Outcome tracking of adverse events 
 Adverse events at the end of the study or not yet relieved must be followed 
until one of the following events occurs: 
 By accident mitigation; 
 Have stable event; 
 when it is not possible to obtain other information (subjects or 
accompanying worker refuse to provide other information to prove after 
follow-up efforts). 
According to the severity of the adverse reactions, the hospital visits, 
outpatient visits, home visits, telephone calls, communications and other 
forms can be adopted.