MAV-RAPA: Prospective Evaluation of the Efficacy of Sirolimus (Rapamune®) in the Treatment of Severe Arteriovenous Malformations

Sponsor

Centre Hospitalier Universitaire, Amiens (Other)

Overall Status

Recruiting

CT.gov ID

NCT02042326

Collaborator

(none)

Enrollment

Locations

Arm

119.7

Anticipated Duration (Months)

3.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Arteriovenous Malformations	Drug: Sirolimus	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 12, 2014

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

Sep 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sirolimus treatment 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 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. Other Names: Rapamune

Arm

Intervention/Treatment

Experimental: Sirolimus treatment

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

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.

Other Names:

Rapamune

Outcome Measures

Primary Outcome Measures

Treatment efficacy at M12 [After 12 months of treatment]
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).

Secondary Outcome Measures

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 [One year]
Number and description of serious advent events
Treatment Impact on Quality of life [Before treatment initiation and after 12 months of treatment]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	UCL	Bruxelles	Belgium
2	CHU Amiens	Amiens	France	80000
3	CHU Bordeaux	Bordeaux	France	33000
4	CHU Dijon	Dijon	France	21000
5	CHRU Lille	Lille	France	59000
6	HCL Lyon	Lyon	France	69000
7	APHM	Marseille	France	13000
8	CHU Montpellier	Montpellier	France	34000
9	CHU Nancy	Nancy	France	54000
10	CHU Nice	Nice	France	06000
11	APHP	Paris	France	75000
12	CHU Strasbourg	Strasbourg	France	67000
13	CHU Tours	Tours	France	37000