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

Study Overview
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Brief Summary
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A prospective, nonrandomized, open-label, single-arm clinical trial to study efficacy of rapamycin (sirolimus) in the treatment of Blue Rubber Bleb Nevus Syndrome, hereditary or sporadic venous malformation

Detailed Description
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Blue rubber bleb nevus syndrome (BRBNS) and venous malformation are mainly caused by somatic mutation of TEK and PIK3CA, which activates the PI3K/AKT signaling pathway. As an important protein kinase downstream of the PI3K/AKT pathway, mTOR can serve as a potential therapeutic target for BRBNS. Experiments of mice have shown that rapamycin inhibited the progression of venous malformation lesions. There are a few human cases reported using rapamycin treatment. The investigator's study is designed to be a prospective, nonrandomized, open-label, single-arm clinical trial to investigate its efficacy and safety.

Official Title
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Efficacy of Rapamycin (Sirolimus) in the Treatment of Blue Rubber Bleb Nevus Syndrome, Hereditary or Sporadic Venous Malformation

Conditions
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Blue Rubber Bleb Nevus Syndrome, Venous Malformation

Intervention / Treatment
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* Drug: Rapamycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with BRBNS, VMCM, sporadic multiple VM, or large single VM; Age and gender are not limited; Physical status ECOG 0 3; Organ function is good, biochemical examination meets the following conditions: AST ≤ 2.5 × upper limit of normal value (ULN), ALT ≤ 2.5 × upper limit of normal value (ULN), serum total bilirubin ≤ 1.5 × upper limit of normal value (ULN), creatinine ≤ 1.5 × upper limit of normal (ULN); Patients volunteer to participate in the trial and sign the informed consent form by the participant or his/her legal guardian. Exclusion Criteria: Patients need emergency surgery due to intestinal obstruction, intussusception, or gastrointestinal bleeding; History of surgery within 1 month; allergic to rapamycin; Any disease or condition that may affect the study implementation or result interpretation, including: known hemoglobinopathy, suffering from gastrointestinal infections at the same time, severe heart, liver, kidney and other serious concomitant diseases that may endanger lives Pregnant or lactating women; Alcohol or drugs (eg, laxatives) abusers; Participating in another clinical trial that may affect this study within one month; Being believed not suitable to be enrolled by the investigator for other reasons. Exit Criteria: An allergic reaction to rapamycin occurs. The patient requests withdrawal: at his own discretion or at the request of his legal representative. Subjects may refuse to participate in further studies at any time without reasons. Subjects will not be affected because of such decision. Subjects are required to withdraw from the study in certain special circumstances (eg, there is significant issues of compliance, safety, or surgical intervention for the disease) 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. Rejection Criteria: Patients who violate the requirements of the test protocol Patients with poor recording (with incomplete, or inaccurate data)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rapamycin<br>For children: rapamycin, 1 mg per square meter of body surface area a day, orally, for at least 6 months For adults: rapamycin, 2 mg a day, orally, for at least 6 months | Drug: Rapamycin<br>* For children: rapamycin, 1 mg per square meter of body surface area a day, orally, for at least 6 months For adults: rapamycin, 2 mg a day, orally, for at least 6 months<br>* Other names: Sirolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total venous malformation lesion load | lesion load (cm2) = A + B + C. A = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by chest, abdomen and pelvis MRI or small bowel CT reconstruction (in cm2) B = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by digestive endoscope (in cm2) C = sum of the product of maximum diameter and maximum height of the largest 3 lesions shown by ultrasound (in cm2) Remarks: 1. If it is impossible to evaluate 3 or more lesions, results of the actual number of lesions should be taken as valid; 2. Lesions evaluated should be correspondent before and after treatment. If the lesion is difficult to assess after treatment, it should be ruled out from the assessment. | The time from start of therapy to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of daily oral iron supplements | The value indicates the amount of gastrointestinal bleeding. | The time from start of therapy to 1 year | 
| Concentration of hemoglobin in blood | The value indicates the amount of gastrointestinal bleeding. | The time from start of therapy to 1 year | 
| Frequency of blood transfusion | The value indicates the amount of gastrointestinal bleeding | The time from start of therapy to 1 year | 
| Concentration of D-dimer in blood | The value indicates the extent of local coagulation caused by Venous Malformation lesions. | The time from start of therapy to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blue Rubber Bleb Nevus Syndrome, Venous Malformation, Rapamycin (sirolimus), Mammalian target of rapamycin (mTOR) inhibitor, Treatment