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出境医 / 临床实验 / Treatment of Congenital Vascular Malformations Using Sirolimus: Improving Quality of Life (Sirolimus)

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

Study Description
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.

Condition or disease Intervention/treatment Phase
Vascular Malformations Drug: Sirolimus Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of Congenital Vascular Malformations Using Sirolimus: Improving Quality of Life
Actual Study Start Date : September 18, 2017
Estimated Primary Completion Date : September 18, 2021
Estimated Study Completion Date : March 1, 2023
Arms and Interventions
Arm Intervention/treatment
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 Name: No other treatment
Outcome Measures
Primary Outcome Measures :
  1. 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)

  2. 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.

  3. 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.

  4. 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)

  5. 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)


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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. 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.

  5. 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.

  6. 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.

  7. 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.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations

Locations
Layout table for location information
Netherlands
Radboudumc, HECOVAN workgroup
Nijmegen, Gelderland, Netherlands, 6500HB
Sponsors and Collaborators
Radboud University
Investigators
Layout table for investigator information
Principal Investigator: Maroeska Loo, te, Dr. Radboud University
Tracking Information
First Submitted Date  ICMJE March 1, 2019
First Posted Date  ICMJE June 14, 2019
Last Update Posted Date January 29, 2021
Actual Study Start Date  ICMJE September 18, 2017
Estimated Primary Completion Date September 18, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2019)
  • 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)
  • 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.
  • 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.
  • 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)
  • 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)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 13, 2019)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Congenital Vascular Malformations Using Sirolimus: Improving Quality of Life
Official Title  ICMJE Treatment of Congenital Vascular Malformations Using Sirolimus: Improving Quality of Life
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Vascular Malformations
Intervention  ICMJE Drug: Sirolimus
Daily intake of Sirolimus during Challenge and Rechallenge phase
Other Name: No other treatment
Study Arms  ICMJE Sirolimus
Sirolimus administration: during Challenge and Rechallenge phase. Compared with the period 2 months before start of Sirolimus.
Intervention: Drug: Sirolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: June 13, 2019) 		75
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 1, 2023
Estimated Primary Completion Date September 18, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03987152
Other Study ID Numbers  ICMJE 57911
2016-002157-38 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Radboud University
Study Sponsor  ICMJE Radboud University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Maroeska Loo, te, Dr. Radboud University
PRS Account Radboud University
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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