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Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care

Primary Purpose

Vascular Malformations

Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Sirolimus
Sponsored by
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Vascular Malformations

Eligibility Criteria

3 Months - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with complex vascular anomalies that are refractory to standard care such as medical treatment, surgical resection and/or sclerotherapy/embolization (ineffective or accompanied by major complications)
  • Patients must have adequate medullary function: Hemoglobine> 10,0 g/dl, neutrophils >1500/mm³ and platelets > 100.000/mm³
  • Patients must have the following laboratory values:
  • Total serum bilirubin ≤ 1.5 x ULN (or totally bilirubin ≤ 3 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with well documented Gilbert Syndrome)
  • Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or < 5.0 x ULN if hepatic metastases are present)
  • Serum creatinine 1.5 x ULN. If the serum creatinine is ≥ 1.5 x ULN, then a 24-hour Creatinine Clearance must be conducted and the result must be ≥ 60 mL/min.
  • Karnofsky > 50
  • Patients have to be able to sign the informed consent
  • Women in age of procreation have to be informed that contraceptive methods are mandatory during the study time

Exclusion Criteria:

  • Any of the following concurrent severe and/or uncontrolled medical conditions, which could compromise participation in the study or interfere with the study results:
  • Impaired cardiac function or clinically significant cardiac diseases, including unstable angina pectoris, ventricular arrhythmia, valvular disease with documented compromise in cardiac function, myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function, history of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy, family history of congenital long or short QT, or known history of QT/QTc prolongation of Torsades de Pointes (TdP)
  • Impairment of Gastro-Intestinal (GI) function or GI disease that may significantly alter the absorption of sirolimus (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea ≥ Grade 2, malabsorption syndrome, or small bowel resection)
  • Known hypersensitivity to drugs or metabolites from similar classes as study treatment.
  • Patient has other concurrent severe and /or uncontrolled medical condition that would,in the investigator's judgment, contraindicated participation in the clinical study (e.g. acute or chronic pancreatitis, liver cirrhosis, active chronic hepatitis, severely impaired lung function with a spirometry ≤ 50% of the normal predicted value and/or O2 saturation ≤ 88% at rest, etc.)
  • Immunocompromised patients, including known seropositivity for HIV
  • Pregnant or lactating women
  • Prior treatment with PI3K and/or mTOR inhibitors

Sites / Locations

  • Cliniques Universitaires Saint-Luc, Université Catholique de Louvain BruxellesRecruiting
  • CHU CaenRecruiting
  • Universitätsklinikum Freiburg

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Patients with vascular malformations

Arm Description

Patients with venous, lympathic or complex vascular malformations (KTS, PTEN, etc.) will receive sirolimus after completion of inclusion criteria

Outcomes

Primary Outcome Measures

Self-assesment (or parent assesment), using visual anagogic scale (0-10) of efficacy of sirolimus
Global treatment efficacy Pain Local complications/symptoms (bleeding, skin tension, esthetic and functional impairment)

Secondary Outcome Measures

Number of enrolled patients with treatment-related adverse events as assessed by CTCAE v4.0
Self assessment of quality of life change induced by sirolimus
Measured by quality of life questionnaire (adapted to MOS SF-36 survey).
Volumetric changes of the malformation on sirolimus, based on magnetic resonance imaging (MRI) 12 months after sirolimus onset.
Relative change of volume of the vascular malformation between the baseline MRI (before sirolimus onset) and the 12-month MRI (during sirolimus treatment)
Efficacy of sirolimus
Change in plasma levels fibrinogen and/ or D-dimers, reflecting improvement in an abnormal intravascular coagulation consumption
Efficacy of sirolimus measured on digital photographs
Qualitative assessment of efficacy on digital photographs

Full Information

First Posted
December 9, 2015
Last Updated
February 23, 2023
Sponsor
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
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1. Study Identification

Unique Protocol Identification Number
NCT02638389
Brief Title
Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care
Official Title
Phase III Multicentric Study Evaluating the Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 25, 2016 (Actual)
Primary Completion Date
April 1, 2025 (Anticipated)
Study Completion Date
April 1, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cliniques universitaires Saint-Luc- Université Catholique de Louvain

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The phosphatidylinositol 3-kinase (PI3Kinase)/Protein Kinase B (AKT)/mammalian target of rapamycin (mTor) pathway plays a role on the development and the venous/lymphatic vascular organisations. The investigators want to study the efficacy and the safety of Rapamycin, an mTor inhibitor.
Detailed Description
The complex vascular malformations induce chronical pains and organic dysfunctions causing significant morbidity and mortality. Therefore, the investigators need to establish guidelines in order to treat these pathologies. Standard treatments such as surgery or interventional radiology are of limited efficacy and related to a high level of recurrences as well as complications. Recent preclinical studies have shown the important role of the PI3Kinase/AKT/mTor pathway on the development and the venous/lymphatic vascular organisations suggesting an appealing therapeutic target to treat patients with venous, lympathic or complex vascular malformations. Investigators will realize a multicentric phase III study enrolling a higher number of patients to statistically evaluate the efficacy and the safety of the Rapamycin, an mTOR inhibitor, in the treatment of children and adults with vascular malformations for which conventional therapies such as surgery or sclerotherapy are ineffective or associated with high risk of important complications. Nearly 250 patients (200 adults and 50 children) will be enrolled in several european centers.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Vascular Malformations

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
250 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Patients with vascular malformations
Arm Type
Experimental
Arm Description
Patients with venous, lympathic or complex vascular malformations (KTS, PTEN, etc.) will receive sirolimus after completion of inclusion criteria
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamycine
Intervention Description
evaluate the efficacy and safety of sirolimus in these patients
Primary Outcome Measure Information:
Title
Self-assesment (or parent assesment), using visual anagogic scale (0-10) of efficacy of sirolimus
Description
Global treatment efficacy Pain Local complications/symptoms (bleeding, skin tension, esthetic and functional impairment)
Time Frame
every 3 months, up to 2-year period.
Secondary Outcome Measure Information:
Title
Number of enrolled patients with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame
every month during the first three months and then every three months for a 2-year-treatment period
Title
Self assessment of quality of life change induced by sirolimus
Description
Measured by quality of life questionnaire (adapted to MOS SF-36 survey).
Time Frame
every 3 months, up to 2-year period.
Title
Volumetric changes of the malformation on sirolimus, based on magnetic resonance imaging (MRI) 12 months after sirolimus onset.
Description
Relative change of volume of the vascular malformation between the baseline MRI (before sirolimus onset) and the 12-month MRI (during sirolimus treatment)
Time Frame
At 12 month
Title
Efficacy of sirolimus
Description
Change in plasma levels fibrinogen and/ or D-dimers, reflecting improvement in an abnormal intravascular coagulation consumption
Time Frame
every three months, up to 2-year period
Title
Efficacy of sirolimus measured on digital photographs
Description
Qualitative assessment of efficacy on digital photographs
Time Frame
every three months, up to 2-year period

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Months
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with complex vascular anomalies that are refractory to standard care such as medical treatment, surgical resection and/or sclerotherapy/embolization (ineffective or accompanied by major complications) Patients must have adequate medullary function: Hemoglobine> 10,0 g/dl, neutrophils >1500/mm³ and platelets > 100.000/mm³ Patients must have the following laboratory values: Total serum bilirubin ≤ 1.5 x ULN (or totally bilirubin ≤ 3 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with well documented Gilbert Syndrome) Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or < 5.0 x ULN if hepatic metastases are present) Serum creatinine 1.5 x ULN. If the serum creatinine is ≥ 1.5 x ULN, then a 24-hour Creatinine Clearance must be conducted and the result must be ≥ 60 mL/min. Karnofsky > 50 Patients have to be able to sign the informed consent Women in age of procreation have to be informed that contraceptive methods are mandatory during the study time Exclusion Criteria: Any of the following concurrent severe and/or uncontrolled medical conditions, which could compromise participation in the study or interfere with the study results: Impaired cardiac function or clinically significant cardiac diseases, including unstable angina pectoris, ventricular arrhythmia, valvular disease with documented compromise in cardiac function, myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function, history of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy, family history of congenital long or short QT, or known history of QT/QTc prolongation of Torsades de Pointes (TdP) Impairment of Gastro-Intestinal (GI) function or GI disease that may significantly alter the absorption of sirolimus (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea ≥ Grade 2, malabsorption syndrome, or small bowel resection) Known hypersensitivity to drugs or metabolites from similar classes as study treatment. Patient has other concurrent severe and /or uncontrolled medical condition that would,in the investigator's judgment, contraindicated participation in the clinical study (e.g. acute or chronic pancreatitis, liver cirrhosis, active chronic hepatitis, severely impaired lung function with a spirometry ≤ 50% of the normal predicted value and/or O2 saturation ≤ 88% at rest, etc.) Immunocompromised patients, including known seropositivity for HIV Pregnant or lactating women Prior treatment with PI3K and/or mTOR inhibitors
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Laurence M. Boon, MD, PhD
Phone
+ 32-2-764 8020
Email
laurence.boon@uclouvain.be
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Laurence M Boon, MD, PhD
Organizational Affiliation
Cliniques universitaires Saint-Luc
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Bruxelles
City
Bruxelles
State/Province
Région De Bruxelles-Capitale
ZIP/Postal Code
1200
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Laurence M Boon, MD, PhD
Phone
+ 32-2-764 8020
Email
laurence.boon@uclouvain.be
First Name & Middle Initial & Last Name & Degree
Emmanuel Seront, MD, PhD
Phone
+ 32-2-764 1992
Email
emmanuel.seront@uclouvain.be
Facility Name
CHU Caen
City
Caen
State/Province
Bretagne
ZIP/Postal Code
14000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anne Dompmartin, MD, PhD
Email
dompmartin-a@chu-caen.fr
First Name & Middle Initial & Last Name & Degree
Fabien Chaillot
Email
chaillot-f@chu-caen.fr
First Name & Middle Initial & Last Name & Degree
Annouk Bisdorff Bresson, MD
First Name & Middle Initial & Last Name & Degree
Isabelle Quere, MD, PhD
First Name & Middle Initial & Last Name & Degree
Philippe Orcel, MD, PhD
First Name & Middle Initial & Last Name & Degree
Marie-Antoinette Sevestre, MD, PhD
First Name & Middle Initial & Last Name & Degree
Anne Dompmartin, MD, PhD
Facility Name
Universitätsklinikum Freiburg
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jochen Roessler, MD, PhD
Email
jochen.roessler@uniklinik-freiburg.de
First Name & Middle Initial & Last Name & Degree
Jochen Roessler, MD, PhD

12. IPD Sharing Statement

Learn more about this trial

Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care

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