A Phase 3 interventional study of Sirolimus in Vascular Malformations, sponsored by Radboud University Medical Center. Status unknown at 1 site in Netherlands. Open to participants aged 1 Year and older. Per ClinicalTrials.gov, last updated 2021-01-29.
Sponsored by Radboud University Medical Center · Phase 3, Interventional, and Treatment
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.
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.
83 studies on the registry are indexed under Vascular Malformations; 28 are open to participants now.
This study's planned enrollment of 75 is above the median of 51 across 48 interventional studies indexed under Vascular Malformations.
Browse Vascular Malformations studies →Radboud University Medical Center is the lead sponsor of 959 studies on the registry; 134 are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 0 (0%) have results posted.
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Exclusion Criteria:
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
Also known as: No other treatment
Quality of life using Sirolimus measured with survey (TAPQOL)
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)
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 using Sirolimus measured with survey (PedsQl)
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.
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 using Sirolimus measured with survey (Research and development Rand-36).
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.
Time frame: 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
Daily pain score (daily visual analogue scale (VAS-score 0-10) for children, and numeric rating scale (NRS-score 0-10) for adults)
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
Difference in pain scores after using Sirolimus measured with NRS score
Daily pain score (daily numeric rating scale (NRS-score 0 no pain -10 extreme pain) for adults)
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
Return of pain after treatment and duration of lowered pain or pain free period in days
Amount of patients who have lowered pain or are pain free. Duration of lowered pain or pain free period in days.
Time frame: After 6 months Sirolimus intake till one year follow up.
Growth/progression of vascular malformation
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.
Time frame: 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
Adverse events: short and long term consequences of treatment with Sirolimus according to CTCAE version 5.0.
Time frame: 4 years
Severity of adverse events related to Sirolimus
Adverse events: short and long term consequences of treatment with Sirolimus according to CTCAE version 5.0.
Time frame: 4 years
Genetic mutations in the vascular malformation that can predict outcome of treatment with Sirolimus using Single Molecule Molecular Inversion Probes (smMIPs)
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.
Time frame: 4 years
Pharmacogenetic profile in the vascular malformation that can predict outcome of treatment with Sirolimus
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.
Time frame: 4 years
Cost-effectiveness of administration of Sirolimus: Quality Adjusted Life Year (QALY) estimate for each patient
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.
Time frame: 4 years
Plan to share: No
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Radboud University Medical Center