Prospective Evaluation of the Efficacy of Sirolimus (Rapamune®) in the Treatment of Severe Arteriovenous Malformations

Study Overview
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Brief Summary
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The aim of the study is to evaluate the efficacy and safety of sirolimus (oral form), to decrease the volume and symptoms due to superficial arteriovenous malformations (AVM). Sirolimus has properties that reduce the activity of the immune system (immunosuppressant), to fight against the proliferation of cancer cells (anti- tumor) and also reduce the proliferation of blood vessels (anti -vascular). Sirolimus is primarily used in transplant patients to prevent organ transplant rejection. Many animal and laboratory studies were carried out and demonstrate in particular the activity of sirolimus on vessels. It is this anti- vascular effect that could help treat arteriovenous malformations.

Detailed Description
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Anti-proliferative and anti-angiogenic properties of Sirolimus (Rapamycin®) are the basis of the rationale to use it in the treatment of arteriovenous malformations, for which the pathophysiology remains poorly understood. The interest of this class of drug is that inhibition of mTOR (mammalian target of rapamycin) may also block growth and / or angiogenic factors (other than VEGF) involved in the development of AVM. More specifically anti-VEGF drugs does not have that potential.

Official Title
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Prospective Evaluation of the Efficacy of Sirolimus (Rapamune®) in the Treatment of Severe Arteriovenous Malformations

Conditions
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Arteriovenous Malformations

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients (adults, adolescents and children older than 2 years), with arteriovenous malformation stage II + III or IV (according to Schöbinger's classification) : active or quiescent, marked or not by hemorrhagic phenomena. Patients (parents for minors) must sign a consent form established after clear information risks and expected benefits of the study. Patients (major and minor of childbearing age) must have effective contraception during the study period and continuing until 12 weeks after the end of treatment Negative pregnancy blood test for women of childbearing age. Exclusion Criteria: Chronic or acquired immunosuppression : patients with transplanted organ or who received a hematopoietic stem cell patient with congenital immunodeficiency Patients implanted with chronic active infection associated with hepatitis B , hepatitis C or HIV Pregnant or nursing woman. Allergy to macrolides Allergy to peanut or soya Hypersensitivity to  Sirolimus  or any of the excipients of the investigational product Contraindications to performing an MRI Leukopenia below 1 000 /mm3 Thrombocytopenia lower to 80,000 /mm3 Anemia with Hb < 9 g/dl Elevated transaminase > 2.5 N History of cancer less than two years before the inclusion Surgery older than 2 months before inclusion Active infection (viral and bacterial ) on the date of inclusion Hypercholesterolemia > 7 mmol / l despite appropriate medical treatment Hyperlipidemia > 2 mmol / l despite appropriate medical treatment Uncontrolled diabetes Patients unable to follow a clinical study Major under guardianship, persons deprived of their liberty

Ages Eligible for Study
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Minimum Age: 2 Years

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: Sirolimus treatment<br>Patients will receive sirolimus (Rapamune). The dose should be adjusted to obtain a residual plasma rate of 8 to 12 ng/ml in 4 weeks. This serum level will be maintained throughout the duration of the study in the absence of side effects. In case of intolerance that do not justify the discontinuation of treatment, the dose may be reduced by maintaining a serum level greater than 3 ng/ml. The starting dose will be 2 mg per day, and will be adapted every week for one month. The preferred dosage form is tablet form. To prevent common side effects in early treatment, corticosteroids based prednisolone (SOLUPRED) will be established at a dose of 0.5 mg/ kg/day for the first week of treatment. | Drug: Sirolimus<br>* For patients with swallowing problems, and for children under 6 years and / or who have an inability to swallow tablets, the 1mg/ml solution form should be used.<br>* Other names: Rapamune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment efficacy at M12 | The efficacy of treatment is a composite criteria based on: The proportion of patients with no evolution of the AVM during the study period, The proportion of patients with a reduction in tumor volume of the AVM at least 30% of CT Angiography (CTA) criteria during the first year of the study (comparison of the volume of the AVM a year versus pre-inclusion). | After 12 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment efficacy at M3 |  | After 3 months of treatment | 
| Treatment efficacy at M6 |  | After 6 months of treatment | 
| Treatment efficacy at M9 |  | After 9 months of treatment | 
| Treatment tolerability | Number and description of serious advent events | One year | 
| Treatment Impact on Quality of life | Quality of life will be assessed before and at the end of the first year of treatment using a questionnaire given to patients. There is no questionnaire specifically tailored to vascular malformations in the literature. Thus the investigators adapted a document based on an evaluation of the quality of life for survivors of burn injury. | Before treatment initiation and after 12 months of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arteriovenous Malformations, Sirolimus, Maxillofacial Surgery