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

NCT03987152 | Unknown Phase 3 DMC

• 2 other identifiers: 579112016-002157-38
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Vascular Malformations

Keywords

Sirolimus; mTor inhibitor; Quality of life; mammalian target of rapamycin (mTOR)

Outcome Measures

Primary Outcomes (5)

• 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)

  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.

  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.

  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)

  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)

  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 Outcomes (7)

• Return of pain after treatment and 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

  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

  4 years

• Severity of adverse events related to Sirolimus

  4 years

• Genetic mutations in the vascular malformation that can predict outcome of treatment with Sirolimus using Single Molecule Molecular Inversion Probes (smMIPs)

  4 years

Study Arms (1)

Sirolimus

OTHER

Sirolimus administration: during Challenge and Rechallenge phase. Compared with the period 2 months before start of Sirolimus.

Drug: Sirolimus

Interventions

Sirolimus DRUG

Daily intake of Sirolimus during Challenge and Rechallenge phase

Also known as: No other treatment

Sirolimus

Eligibility Criteria

• Age: 1 Year+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboudumc, HECOVAN workgroup

Nijmegen, Gelderland, 6500HB, Netherlands

Location

Related Publications (1)

• Harbers VEM, Bouwman FCM, van Rijnsoever IMP, Verhoeven BH, van der Vleuten CJM, Schultze Kool LJ, de Laat PCJ, van der Horst CMAM, Kievit W, Te Loo DMWM. Magnitude and relevance of change in health-related quality of life in patients with vascular malformations treated with sirolimus. Front Med (Lausanne). 2023 Apr 20;10:1155476. doi: 10.3389/fmed.2023.1155476. eCollection 2023.

  PMID: 37153086 DERIVED

MeSH Terms

Conditions

Vascular Malformations; Hereditary Sensory and Autonomic Neuropathies

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Maroeska Loo, te, Dr.

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Challenge-Dechallenge-Rechallenge design All patients receive Sirolimus during challenge phase (6 months), stop Sirolimus during dechallenge phase (12 months), and if pain/symptoms returns Sirolimus intake is restarted during the rechallenge phase.

Study Record Dates

• First Submitted: March 1, 2019
• First Posted: June 14, 2019
• Study Start: September 18, 2017
• Primary Completion: September 18, 2021
• Study Completion: March 1, 2023
• Last Updated: January 29, 2021

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)