Treatment of Congenital Vascular Malformations Using Sirolimus: Improving Quality of Life (Sirolimus)

January 28, 2021 updated by: Radboud University Medical Center
Congenital vascular anomalies are uncommon and belong to the group of rare diseases.These vascular malformations can cause serious complications including obstruction of vital organs and their function, recurrent infection and significantly reduced quality of life of persons affected.Treatment options range from conservative to surgical extirpation or intralesional embolisation/sclerosis. Unfortunately, this is often not enough. Many patients still have complaints like severe pain and invalidation due to the lymphatic or venous malformation making a normal functional life impossible. Recent case reports mention the positive effects of refractory patients with Sirolimus. Sirolimus, also known as rapamycin, is currently the only FDA-approved mammalian target of rapamycin (mTOR) inhibitor.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Congenital vascular anomalies are uncommon and belong to the group of rare diseases. In 1996, the International Society of the Study of Vascular Anomalies adopted a new classification, distinguishing vascular malformations from vascular tumors. This classification was revised in 2014 and newly identified genetic features were taken into account. Vascular malformations feature dysplastic malformed vessels and are a consequence of a defective development of the embryonic vascular system. Vascular malformations can involve lymphatic vessels, capillaries, veins and arteries or even combinations. These vascular malformations are present at birth and grow with the child. Treatment options range from conservative to surgical extirpation or intralesional embolisation/sclerosis. Unfortunately, this is often not enough. Many patients still have complaints like severe pain and invalidation due to the lymphatic or venous malformation making a normal functional life impossible. These vascular malformations can cause serious complications including obstruction of vital organs and their function, recurrent infection and significantly reduced quality of life of persons affected. As the natural course of the disease affects multiple body systems, the therapeutic management is challenging. To date, no other medical treatment options are available. Although standard pain medication is given according the (inter) national pain protocols, patients still suffer pain and are not able to function normally in daily life. Majority (60-70% percent of the patients) of the patients is not able to have a normal life, with a normal job and normal social activities. Children are often not able to go to school normally, cannot play outside and have pain at the site of the malformation. The vast majority of literature reporting medical therapies for vascular anomalies consists of case reports and small series and is complicated by publication bias (negative findings are often not published), inconsistent use of nomenclature, and the absence of clinical trials. Recent case reports mention the positive effects of refractory patients with Sirolimus. Sirolimus, also known as rapamycin, is currently the only FDA-approved mammalian target of rapamycin (mTOR) inhibitor, indicated for prevention of kidney allograft rejection in adults and children 13 years or older, but is commonly used to manage organ rejection in younger children.

Study Type

Interventional

Enrollment (Anticipated)

75

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6500HB
        • Radboudumc, HECOVAN workgroup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Diagnosis of Congenital venous malformation, or lymphatic malformation or combined.
  • Age older than 1 yr.
  • Patients (or legal guardians for children) have to be able to sign the informed consent
  • Patients are either refractory to standard care such as medical treatment (low molecular weight heparins, pain medication etc.), surgical resection and/or sclerotherapy/embolization (ineffective or accompanied by major complications) or there is no possibility for surgical intervention anymore. Only patients that have a normal clinical screening (no signs for infection, normal bone marrow function, normal liver and kidney function, normal glucose metabolism etc.) can be included.
  • Patients included have no cardiac impairment
  • Patients have no gastrointestinal impairment as Sirolimus is absorbed gastro-intestinal and normal function is needed
  • No other underlying medical disorder like Down syndrome or other syndromes
  • Women of reproductive age have to be informed that contraceptive methods are
  • mandatory during the study time, pregnant women are excluded
  • Karnofsky score > 50

Exclusion Criteria:

  • No written informed consent
  • 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.)
  • Recent history of primary malignancy ≤ 5 years
  • Impaired cardiac function or clinically significant cardiac diseases
  • Immunocompromised patients, including known seropositivity for HIV
  • Patient with any other concurrent severe and /or uncontrolled medical condition that would,in the investigator's judgment, contraindicated participation in the clinical study.
  • Pregnant or lactating women
  • Karnofsky score < 50

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Sirolimus
Sirolimus administration: during Challenge and Rechallenge phase. Compared with the period 2 months before start of Sirolimus.
Drug: Sirolimus
Daily intake of Sirolimus during Challenge and Rechallenge phase
Other Names:
  • No other treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quality of life using Sirolimus measured with survey (TAPQOL)
Time Frame: Change from baseline Quality of life at 6 months QoL in challenge phase, and 12 months QoL in Rechallenge phase.
Quality of life: Questionnaire for Preschool Children's Health-Related Quality of Life (TAPQOL). Preschool Children Quality of Life, parent-reported questionnaire clustered into 12 multi-item scales, with higher scores range 0-100) indicating better HRQOL)
Change from baseline Quality of life at 6 months QoL in challenge phase, and 12 months QoL in Rechallenge phase.
Quality of life using Sirolimus measured with survey (PedsQl)
Time Frame: Change from baseline Quality of life at 6 months QoL in challenge phase, and 12 months QoL in Rechallenge phase.
Quality of life: Pediatric Quality of Life Inventory (PedsQl) (children) 23 items questionnaire, 0-100 scale, so that higher scores indicate better HRQOL (Health-Related Quality of Life). Psychosocial Health Summary Score, Physical Health Summary Score and Total score will be measured.
Change from baseline Quality of life at 6 months QoL in challenge phase, and 12 months QoL in Rechallenge phase.
Quality of life using Sirolimus measured with survey (Research and development Rand-36).
Time Frame: hange from baseline Quality of life at 6 months QoL in challenge phase, and 12 months QoL in Rechallenge phase
Quality of life: Rand-36 (adults) eight health domains; physical functioning, social functioning, role limitations due to physical health problems, role limitations due to emotional problems, mental health, vitality, pain and general health perception. Outcomes at each domain will be defined on a scale from a minimum score of 0 to a maximum score of 100. A higher score is equivalent to a better health.
hange from baseline Quality of life at 6 months QoL in challenge phase, and 12 months QoL in Rechallenge phase
Difference in pain scores after using Sirolimus measured with VAS score
Time Frame: Daily pain scores will be compared after 6 months in Challenge phase, after Challenge phase: starts the phase, and pain during 12 months in the Rechallenge phase
Daily pain score (daily visual analogue scale (VAS-score 0-10) for children, and numeric rating scale (NRS-score 0-10) for adults)
Daily pain scores will be compared after 6 months in Challenge phase, after Challenge phase: starts the phase, and pain during 12 months in the Rechallenge phase
Difference in pain scores after using Sirolimus measured with NRS score
Time Frame: Daily pain scores will be compared after 6 months in Challenge phase, after Challenge phase: starts the phase without Sirolimus treatment, and pain during 12 months in the Rechallenge phase
Daily pain score (daily numeric rating scale (NRS-score 0 no pain -10 extreme pain) for adults)
Daily pain scores will be compared after 6 months in Challenge phase, after Challenge phase: starts the phase without Sirolimus treatment, and pain during 12 months in the Rechallenge phase

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Return of pain after treatment and duration of lowered pain or pain free period in days
Time Frame: After 6 months Sirolimus intake till one year follow up.
Amount of patients who have lowered pain or are pain free. Duration of lowered pain or pain free period in days.
After 6 months Sirolimus intake till one year follow up.
Growth/progression of vascular malformation
Time Frame: MRI baseline compared with MRI after 6 months in challenge phase and 12 months in rechallenge phase
MRI of the vascular malformation will be made at the beginning of the study and after six months of treatment with Sirolimus. An experienced radiologist will evaluate the evolution of the volume of the malformation.
MRI baseline compared with MRI after 6 months in challenge phase and 12 months in rechallenge phase
Rate and occurence of adverse events related to Sirolimus
Time Frame: 4 years
Adverse events: short and long term consequences of treatment with Sirolimus according to CTCAE version 5.0.
4 years
Severity of adverse events related to Sirolimus
Time Frame: 4 years
Adverse events: short and long term consequences of treatment with Sirolimus according to CTCAE version 5.0.
4 years
Genetic mutations in the vascular malformation that can predict outcome of treatment with Sirolimus using Single Molecule Molecular Inversion Probes (smMIPs)
Time Frame: 4 years
Secondary material that was obtained after surgery, stored in the HECOVAN biobank can be used for analyses. Comprehensive targeted Next Generation Sequencing screen using Unique Molecular Identifiers with a technical sensitivity of 1% mutant alleles was performed for frequently mutated positions using Single Molecule Molecular Inversion Probes. We will investigate if there is a correlation with a possible found mutation and painreduction or improvement of quality of life.
4 years
Pharmacogenetic profile in the vascular malformation that can predict outcome of treatment with Sirolimus
Time Frame: 4 years
Genotyping will be performed using Taqman assays or Kompetitive Allele Specific PCR (KASPTM) assays in saliva swabs. Pharmacogenetic profiles (slow, intermediate, and extensive metabolizer) will be determined. Subjects compared on the outcome of sirolimus effectiveness for pain, and QoL stratified by CYP3A4.
4 years
Cost-effectiveness of administration of Sirolimus: Quality Adjusted Life Year (QALY) estimate for each patient
Time Frame: 4 years
Via standardized questionnaires developed by the iMTA (institute for Medical Technology Assessment). The second part of the cost analysis consists of determining the cost prices for each volume of consumption.
4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Investigators

  • Principal Investigator: Maroeska Loo, te, Dr., Radboud University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 18, 2017

Primary Completion (Anticipated)

September 18, 2021

Study Completion (Anticipated)

March 1, 2023

Study Registration Dates

First Submitted

March 1, 2019

First Submitted That Met QC Criteria

June 13, 2019

First Posted (Actual)

June 14, 2019

Study Record Updates

Last Update Posted (Actual)

January 29, 2021

Last Update Submitted That Met QC Criteria

January 28, 2021

Last Verified

October 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 57911
  • 2016-002157-38 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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