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

Primary Purpose

Arteriovenous Malformations

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Sirolimus
Sponsored by
Centre Hospitalier Universitaire, Amiens
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Arteriovenous Malformations focused on measuring Arteriovenous Malformations, Sirolimus, Maxillofacial Surgery

Eligibility Criteria

2 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • UCL
  • CHU AmiensRecruiting
  • CHU Bordeaux
  • CHU DijonRecruiting
  • CHRU Lille
  • HCL LyonRecruiting
  • APHM
  • CHU Montpellier
  • CHU Nancy
  • CHU Nice
  • APHP
  • CHU Strasbourg
  • CHU Tours

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sirolimus treatment

Arm Description

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Treatment efficacy at M3
Treatment efficacy at M6
Treatment efficacy at M9
Treatment tolerability
Number and description of serious advent events
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.

Full Information

First Posted
January 20, 2014
Last Updated
February 7, 2023
Sponsor
Centre Hospitalier Universitaire, Amiens
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1. Study Identification

Unique Protocol Identification Number
NCT02042326
Brief Title
Prospective Evaluation of the Efficacy of Sirolimus (Rapamune®) in the Treatment of Severe Arteriovenous Malformations
Acronym
MAV-RAPA
Official Title
Prospective Evaluation of the Efficacy of Sirolimus (Rapamune®) in the Treatment of Severe Arteriovenous Malformations
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 12, 2014 (Actual)
Primary Completion Date
September 2024 (Anticipated)
Study Completion Date
September 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre Hospitalier Universitaire, Amiens

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Arteriovenous Malformations
Keywords
Arteriovenous Malformations, Sirolimus, Maxillofacial Surgery

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Sirolimus treatment
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamune
Intervention Description
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.
Primary Outcome Measure Information:
Title
Treatment efficacy at M12
Description
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).
Time Frame
After 12 months of treatment
Secondary Outcome Measure Information:
Title
Treatment efficacy at M3
Time Frame
After 3 months of treatment
Title
Treatment efficacy at M6
Time Frame
After 6 months of treatment
Title
Treatment efficacy at M9
Time Frame
After 9 months of treatment
Title
Treatment tolerability
Description
Number and description of serious advent events
Time Frame
One year
Title
Treatment Impact on Quality of life
Description
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.
Time Frame
Before treatment initiation and after 12 months of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bernard DEVAUCHELLE, MD, PhD
Phone
+33322668325
Email
devauchelle.bernard@chu-amiens.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Sylvie TESTELIN, MD, PhD
Email
testelin.sylvie@chu-amiens.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bernard DEVAUCHELLE, MD, PhD
Organizational Affiliation
CHU Amiens
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Emmanuel MORELON, MD, PhD
Organizational Affiliation
HCL Lyon
Official's Role
Study Chair
Facility Information:
Facility Name
UCL
City
Bruxelles
Country
Belgium
Individual Site Status
Not yet recruiting
Facility Name
CHU Amiens
City
Amiens
ZIP/Postal Code
80000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bernard DEVAUCHELLE, MD, PhD
First Name & Middle Initial & Last Name & Degree
Sylvie TESTELIN, MD, PhD
Facility Name
CHU Bordeaux
City
Bordeaux
ZIP/Postal Code
33000
Country
France
Individual Site Status
Not yet recruiting
Facility Name
CHU Dijon
City
Dijon
ZIP/Postal Code
21000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pierre VABRES, MD PhD
First Name & Middle Initial & Last Name & Degree
Pierre VABRES, MD PhD
Facility Name
CHRU Lille
City
Lille
ZIP/Postal Code
59000
Country
France
Individual Site Status
Not yet recruiting
Facility Name
HCL Lyon
City
Lyon
ZIP/Postal Code
69000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pierre BRETON, MD PhD
Email
pierre.breton@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Laurent GUIBAUD, MD PhD
Email
laurent.guibaud@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Pierre BRETON
First Name & Middle Initial & Last Name & Degree
Laurent GUIBAUD
Facility Name
APHM
City
Marseille
ZIP/Postal Code
13000
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stéphanie MALLET, MD
Email
stephanie.mallet@ap-hm.fr
First Name & Middle Initial & Last Name & Degree
Jean-Michel BARTOLI
First Name & Middle Initial & Last Name & Degree
Stéphanie MALLET, MD
Facility Name
CHU Montpellier
City
Montpellier
ZIP/Postal Code
34000
Country
France
Individual Site Status
Not yet recruiting
Facility Name
CHU Nancy
City
Nancy
ZIP/Postal Code
54000
Country
France
Individual Site Status
Not yet recruiting
Facility Name
CHU Nice
City
Nice
ZIP/Postal Code
06000
Country
France
Individual Site Status
Not yet recruiting
Facility Name
APHP
City
Paris
ZIP/Postal Code
75000
Country
France
Individual Site Status
Not yet recruiting
Facility Name
CHU Strasbourg
City
Strasbourg
ZIP/Postal Code
67000
Country
France
Individual Site Status
Not yet recruiting
Facility Name
CHU Tours
City
Tours
ZIP/Postal Code
37000
Country
France
Individual Site Status
Not yet recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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