Efficacy of Rapamycin (Sirolimus) in the Treatment of Blue Rubber Bleb Nevus Syndrome, Hereditary or Sporadic Venous Malformation
Phase: PHASE4
Conditions: Blue Rubber Bleb Nevus Syndrome, Venous Malformation
Sponsor: Peking Union Medical College Hospital

 
 
 
 
 
Efficacy of Rapamycin (Sirolimus) in 
the Treatment of BRBNS, Hereditary 
or Sporadic Venous Malformation 
 
 
(December 5, 2018) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
I. 
Background 
II. 
Objective 
III. Research 
IV. Selection of subjects 
V. 
Therapeutic schedule 
VI. Follow-up plan and content 
VII. Records and reports of adverse events 
VIII. Statistical analysis 
IX. Measures of quality control 
X. 
Expected research results 
XI. Potential risks, benefits or advantages of this study 
XII. Data preservation and confidentiality 
XIII. Measures to protect subjects and minimize risks 
 
 
 
 
 

I. Background 
Blue rubber bleb nevus syndrome (BRBNS) is a rare systemic syndrome featuring venous 
malformation and hemangiomas. Affected organs include skin and gastrointestinal tract. 
Patients manifest venous malformation (VM) at birth. Main histologic features of VM are 
dilated and distorted veins surrounded by sparse and irregular smooth muscle cells. The size 
and number of VM lesions in BRBNS increase gradually with age. Patents’ skin develops 1-
2cm of blue-violet, compressible, and hyperkeratotic VM lesions, mostly in palms and soles. 
Lesions cause local deformity, pain and intravascular coagulopathy. The latest menifests 
elevated D-dimers and may lead to disseminated intravascular coagulation (DIC). Risk of DIC 
is even higher under surgical treatment. Lesions of BRBNS can be found in the mucosa of the 
whole gastrointestinal tract. Small intestine is the most commonly affected organ. Lesions can 
cause gastrointestinal bleeding, intussusception, intestinal torsion and even intestinal necrosis[1]. 
Due to long-term chronic gastrointestinal bleeding, many patients need to take life-long iron 
supplementary treatment and receive blood transfusions repeatedly. VM lesions of BRBNS can 
also affect organs in pelvic, abdominal and thoracic cavity. BRBNS is such a devastating 
disease, traditional drugs such as glucocorticoids, interferon-α, propranolol and intravenous 
iron are not effective. Besides surgical resection of affected tissue and repeated sclerotherapy, 
there is no validated targeted drug treatment. 
Sporadic BRBNS cases have been reported. There are also a few familial cases consistent 
with autosomal dominant inheritance pattern[2-6]. Soblet et al[1] show that BRBNS is caused by 
somatic mutation of TEK gene, which encodes a receptor of angiogenin, endothelial tyrosine 
kinase receptor TIE2. Multifocal VM lesions of BRBNS patients are caused by double (cis) 
mutations, i.e., two somatic mutations on the same allele of the gene. Germline mutations of 
TEK gene can cause venous malformation, cutaneous and mucosal (VMCM), a rare autosomal 
dominant hereditary disease. Several repetitive mutation sites of TEK gene have been observed 
in sporadic BRBNS patients[1]. These mutations result in ligand-independent activation of TIE2 
and PI3K/AKT signaling pathways, which in turn promote cell survival, migration, invasion 
and colonization. 
In addition to multifocal VM lesions, Soblet et al. also foumd that about 20% of unifocal 
VM patients carry PIK3CA gene (encoding Class I p110α catalytic subunit of PI3K) mutation, 
which also activates the PI3K/AKT signaling pathway. Clinically, venous malformation 
diseases caused by TIE2 and PIK3CA somatic mutations are almost indistinguishable, 
suggesting that the PI3K/AKT signaling pathway plays a key role in BRBNS[1]. 
An important protein kinase mTOR (mammalian target of rapamycin) downstream of the 
PI3K/AKT pathway can serve as a potential therapeutic target for the venous malformation 
syndromes mentioned above. Experiments on mice have shown that mTOR inhibitor rapamycin 
can control the progression of VM lesions. It can also relieve VM lesions caused by PIK3CA 
and TEK mutations in humans[7]. There are a few cases reported using rapamycin (sirolimus) 
as treatment, and achieving satisfactory effects without significant adverse events[8-11]. Large-
scale prospective studies are needed to demonstrate the efficacy of rapamycin for BRBNS. 
 
II. Objective 

1. To evaluate the safety of sirolimus in treatment of blue rubber blisters syndrome (BRBNS), 
hereditary cutaneous and mucosal venous malformation (VMCM), and sporadic multiple 
VM. 
2. To evaluate the efficacy of sirolimus in treatment of blue rubber blisters syndrome 
(BRBNS), hereditary cutaneous and mucosal venous malformation (VMCM), and sporadic 
multiple VM. 
 
III. Research Design 
1. This study is a prospective, nonrandomized, open-label, single-arm clinical trial. The 
sirolimus capsule (Rapamycin, Yixinke®), 0.5 mg/grain*20/box, is produced by North 
China Pharmaceutical Co., Ltd. 
2. All patients who meet inclusion criteria and sign informed consents receive sirolimus 
treatment for at least 6 months. Patients are followed up in a regular schedule. 
3. No less than 20 patients should be enrolled. 
 
IV. Selection of subjects 
A. Inclusion criteria 
(1) Patients diagnosed with BRBNS, VMCM, sporadic multiple VM, or large single VM; 
(2) Age and gender are not limited; 
(3) Physical status ECOG 0~3; 
(4) Organ function is good, biochemical examination meets the following conditions:  
a) AST ≤ 2.5 × upper limit of normal value (ULN),  
b) ALT ≤ 2.5 × upper limit of normal value (ULN),  
c) serum total bilirubin ≤ 1.5 × upper limit of normal value (ULN),  
d) creatinine ≤ 1.5 × upper limit of normal (ULN); 
(5) Patients volunteer to participate in the trial. Participant or his/her legal guardian signs 
the informed consent form. 
B. Exclusion criteria 
(1) Patients need emergency surgery due to intestinal obstruction, intussusception, or 
gastrointestinal bleeding; 
(2) History of surgery within 1 month; 
(3) Allergic to rapamycin; 
(4) Any disease or condition that may affect the study implementation or result 
interpretation, including: 
a) known hemoglobinopathy 
b) concomitant gastrointestinal infections 
c) severe heart, liver, kidney and other serious concomitant diseases that may 
endanger lives 
(5) Pregnant or lactating women; 
(6) Alcohol or drugs (eg, laxatives) abusers; 
(7) Participate in another clinical trial that may affect his or her study within one month; 
(8) The investigator believes to be not suitable for other reasons. 

C. Exit criteria 
(1) An allergic reaction occurs. 
(2) The patient requests withdrawal: at his or her own discretion or at the request of his or 
her legal representative. Subjects may refuse to participate in further studies at any time 
without providing reasons. Subjects will not be affected because of such decision. 
(3) Subjects are required to withdraw from the study in certain special circumstances (eg, 
there is significant issues of compliance, safety, or surgery for venous malformations) 
(4) Other situations in which the study must be terminated. For example, the investigators 
believe that continuing the study may be harmful to the health of subjects. 
D. Rejection criteria 
(1) Patients who violate the requirements of the test protocol 
(2) Patients with poor-recording, incomplete, or inaccurate data 
 
V. Therapeutic schedule 
A. Enrollment 
Before starting the study, the investigator clearly and colloquially explains the study and its 
potential risks and benefits to the patient or his/her authorizer. Patient or his/her authorized and 
the investigator sign and date the informed consent form. Only after signing the informed 
consent form can patient or his/her authorizer enter the screening section. Patients who sign a 
written informed consent need to be assessed to determine if the patient meets the study criteria: 
1) Demographic data and medical history of the patient; 
2) vital signs; 
B. Children’s dosage regimen 
Oral administration 
The initial dose of oral rapamycin intake is 1 mg/m2 of body surface area. Drug trough 
concentration in patient's blood is maintained at 5-10 ng/ml. 
C. Adults’ dosage regimen 
Oral administration 
1) Initial dose and dosing schedule: sirolimus 2mg, once a day. Maintain drug trough 
concentration of 5-10ng / mL in blood. If adverse events are too severe to tolerate, daily 
dosage can be reduced by 0.5mg every week. The minimum dosage is 1 mg/day. If patient 
still cannot tolerate minimum dosage, withdraw from the study. If patient could tolerate the 
possible adverse events, continue to take the original dose for 3 months, and evaluate 
improvement of disease condition. 
2) Subsequent dose and dosing schedule: After taking sirolimus 2 mg once a day for 3 months, 
those with improved condition continue to take the original dose. If improvement of disease 
condition is not obvious, change dosage to 2.5mg-3mg once a day. If this dosage cannot be 
tolerated, patients may withdraw from the study. If it can be tolerated, continue to take for 
another 3 months and reassess the improvement of condition. 
3) Blood drug concentration test: Blood samples are taken at 1st, 3rd and 6th months of 
dosage schedule.  
4) Iron supplementation: For subjects with hemoglobin ≤ 10.9 g / dl, iron supplementation 
should be provided according to the standard dosing regimen, but iron supplementation is 

not considered as study treatment and will be recorded as concomitant medication. 
 
VI. Follow-up plan and content 
A. Evaluation before the trial 
Each subject should complete the following items in four weeks before the treatment: 
1) Complete medical history 
2) Detailed personal profile 
3) VAS pain score 
4) Quality of Life (Qol) Rating Scale 
5) Frequency of blood transfusion therapy 
6) A physical examination 
7) Blood and urine routine examination 
8) Liver and kidney function, blood lipid test 
9) Coagulation I+D dimer examination 
10) abdominal and pelvic cavity contrast-enhanced CT + small intestine reconstruction CT 
examination (for patients with gastrointestinal system affected) 
11) Digestive system endoscopy (for patients with gastrointestinal system affected) 
12) Ultrasound, MRI examination of the lesion 
13) (Female of childbearing age) blood/urine pregnancy test 
B. Evaluation during sirolimus treatment 
Adverse reactions are evaluated weekly during the first month of drug treatment. The efficacy 
and safety are then evaluated at the 3rd and 6th months, and the content of the examination is 
the same as the pre-trial evaluation. 
1) Efficacy assessment: 
a. Clinical symptom assessment (including VAS pain score, gastrointestinal bleeding, 
quality of life (Qol) evaluation, frequency of blood transfusion treatment and other 
related symptoms); 
b. Changes in hemoglobin; 
c. Coagulation I+D-dimer examination; 
d. Nutritional status (including albumin, etc.); 
e. Ultrasound, MRI examination of the lesion, abdominal and pelvic cavity contrast-
enhanced CT + small intestine reconstruction CT examination, digestive system 
endoscopy to measure the size, quantity and total load of VM lesions; 
2) Safety assessment: Safety parameters (such as asking adverse events, measuring 
laboratory values, vital signs, gastrointestinal bleeding, etc.) will be closely monitored on 
a regular basis throughout the study. 
3) Treatment compliance: In order to monitor compliance, subjects are required to complete 
an electronic diary during the entire study period. Dates of drug intake will be tracked by 
this diary. At every visit, the investigator and the subject will review the electronic diary 
data together. 
C. Evaluation after treatment 
Evaluation of curative effects and safety is conducted at the end of the drug therapy, six and 
twelve months after the treatment. Its content is the same as pre-trial evaluation. 

 
VII. Records and reports of adverse events 
A. Adverse events 
The term of adverse events encompass any signs, symptoms, syndromes or diseases affecting 
health condition of subjects during the trial. The term also includes clinically relevant 
conditions found by laboratory test or other diagnostic procedures. It may call for unplanned 
treatment, or lead to withdrawal from the trial. Adverse events may be: new disease; 
deterioration of symptoms accompanying disease progression during treatment; certain events 
not related to the trial; combination of one or more events above.  
Serious adverse events 
At any dose of the test drug or at any time during the observation period, the following 
adverse events occurs: death; immediate life-threatening events; requirement of 
hospitalization or prolonged hospital stay; disability; congenital malformations; other events 
with important medical implications (those do not immediately endanger life or cause death 
or require hospitalization, but may harm the patient or require interventions to prevent one of 
the consequences defined above) and requiring medical treatment to prevent permanent 
injury. 
B. Adverse reactions 
Harmful and unexpected reactions caused by pharmaceutical applications under normal use of 
drugs and prescribed doses. 
C. Degree of adverse reactions: 
1) Mild: causing mild discomfort which can be tolerated and does not affect daily life; under 
this circumstance, the subject does not need to discontinue medication. 
2) Moderate: causing discomfort which affects patients’ daily life. 
3) Severe: affecting daily life; cannot be endured by the subject or cause organ damage and 
need to withdraw medication. 
4) Very serious: risk of disability or death; require emergent rescue and drug withdraw.  
D. Evaluation of the relationship between adverse reactions and experimental drug 
According to the 5-level judgment system, the relationships can be divided into 5 types: 
definitely related, very likely related, may be related, may be irrelevant, and definitely 
irrelevant. The first three are counted as adverse reactions, in which case the incidence of 
adverse reactions and adverse events should be reported. 
D. Record and report 
The investigator should explain to the patient or his/her legal guardian that it is required to 
truthfully reflect the changes in the condition after administration. Doctors should avoid 
suggestive questions. While observing the efficacy, pay close attention to the observation of 
adverse events or unanticipated side effects (including symptoms, signs, laboratory tests), 
analyze the causes, make judgments, and report the incidence of adverse reactions and 
adverse events. 
For adverse events occurring during the trial, time, symptoms, extent, duration, treatment 
measures, outcomes, and some other items should be recorded in the case report form to 
evaluate the correlation with the test drug. Investigator should record it in detail, and then 
signs and dates. 

E. Treatment of adverse events 
1) reporting system 
Any adverse events, such as subjective discomfort and abnormal laboratory tests, should be 
taken seriously and carefully analyzed. Immediate measures should be taken to protect safety 
of the subject. 
2) treatment procedure 
Physicians are pre-trained to prevent certain types of adverse events or reactions that may 
occur in the study, so as to protect safety of patients. Treatment procedure of adverse event 
should be recorded in detail. Persistence and disappearance of adverse events should also be 
recorded. 
3) treatment of serious adverse events 
On the occurrence of any serious adverse event, research physician should report to primary 
PI within 24 hours, in addition to emergency treatment. 
4) follow-up of unresolved adverse events 
All adverse events should be tracked until they are properly resolved. Adverse events with 
abnormal laboratory values should be tracked until the value returns to baseline. 
 
VIII. Statistical analysis  
Statistical analysis will be conducted by SPSS.  
A. Methods of statistical analysis   
The categorical variables will be described by frequency distribution (number of cases and 
percentage). Continuous variables will be described with mean, median, minimum, 
maximum, first and third quartile. The confidence interval of all parameters is set to be 95%. 
All analyses will be conducted with SPSS.  
B. Contents of statistical analysis   
1) General data analysis: Demographic variables and baseline characteristics will be 
summarized comprehensively by mean of descriptive statistics and/or appropriate frequency 
tables.  
2) Evaluation of efficacy: According to follow-up and reexamination results, the patients’ 
quality of life, size and volume of the lesions, tumor load control and improvement of 
symptoms will be analyzed.  
3) Analysis of adverse events: Side effects and adverse events during medication will be 
assessed.  
4) Evaluation of the relationship between adverse events and the tested drug  
 
IX. Measures of quality control  
1. Supervision by the project leader  
2. Establish a standardized evaluation method, unify various diagnostic criteria and efficacy 
criteria 
3. Formulate plans for monitoring and treatment of adverse reactions  

4. All researchers are trained before the study begun 
5. Designate quality controllers and develop a plan for quality control, with regular 
inspections  
6. Devise a follow-up plan and system  
 
X. Expected research results  
The results will be published in a paper and fed back to the subjects.  
 
XI. Potential risks, benefits or advantages of this study  
As a drug that has been on the market for years, it is applied to this study beyond its 
indication. It is recommended by doctors considering that its benefits outweigh its risks and 
the subjects have no better choice. For subjects, it may relieve their symptoms and improve 
quality of life, and complications associated with surgery and damage to intestinal function 
can be avoided. The testing drug is free during the study and subjects should bear the risks of 
treatment.  
 
XII. Data preservation and confidentiality  
It will be stated in the informed consent that personal information of subjects will be strictly 
confidential in this study. Results of this study may be published in scientific paper, but 
personal information of subjects, including their names, will not appear in the paper. All data 
relevant to this study will be preserved by Peking Union Medical College Hospital and 
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, and strict 
confidentiality measures will be established.  
 
XIII. Measures to protect subjects and minimize risks  
In the whole course of this study, safety supervision will be carried out by experts from the 
digestive surgery department of our hospital to strictly control diagnostic criteria and 
treatment indicators of BRBNS, VMCM and VM, making the collected clinical data meet 
international diagnostic criteria and providing favorable treatment for these patients.