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Trial registered on ANZCTR


Registration number
ACTRN12616000943448
Ethics application status
Approved
Date submitted
27/06/2016
Date registered
15/07/2016
Date last updated
28/11/2019
Date data sharing statement initially provided
28/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
5 year study of 6 children each year with vascular anomalies who have severe complications failing to respond to the usual treatments will be offered a new use of an old medication- sirolimus
Scientific title
Role of sirolimus in management of complex vascular anomaliesin children: Complex venous, lymphatic malformations, Vascular tumours- kaposiform haemangioendotheliomas, Generalised lymphatic anomalies and PIKC3A related overgrowth syndromes.
Secondary ID [1] 289555 0
Nil Known
Secondary ID [2] 289665 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Complex vascular malformations 299275 0
Complex lymphatic malformations 299276 0
Vascular tumours (tufted angiomas and kaposiform haemangioendotheliomas) 299277 0
Generalised lymphatic anomalies 299278 0
PIKC3A related overgrowth syndrome (PROS) 299279 0
Condition category
Condition code
Cardiovascular 299276 299276 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment with sirolmus ( dose of sirolimus will be calculated based on the surface area of the child (0.8mg/m2/dose twice daily). Its an orally administered medication. Pre-treatment blood and relevant imaging tests will be conducted. Blood levels of sirolimus will be monitored along with other blood tests at regular intervals. Target sirolimus level s will be 10-15 micrograms/litre. The duration of treatment with sirolimus will be 12 months. Sirolimus is an immune modulator so there is a risk of Pneumocystis Carinii pneumonia so prophylaxis in the form of co-trimoxazole (Bactrim) 2.5mg/kg/dose, administered orally in the form of tablet or suspension twice daily three times a week on Mondays, Wednesdays and Fridays will be prescribed for all the patients while on sirolimus (12 months or as long as they are on sirolimus).

Educating children and parents related to the importance of adherence prior to commencement of sirolimus and frequent follow up /blood sirolimus monitoring at regular intervals to ensure complianace.
Intervention code [1] 295146 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298752 0
Coagulopathy will be assessed by regular blood coagulation profile studies, baseline prior to commencement of sirolimus, at weekly intervals during the first month, monthly for 3 months and then every 3 months throughout the period of treatment (12 months).
Timepoint [1] 298752 0
12 months
This will be assessed by regular blood coagulation profile studies, baseline prior to commencement of sirolimus, at weekly intervals during the first month, monthly for 3 months and then every 3 months throughout the period of treatment (12 months).
Primary outcome [2] 298949 0
Pain will be assesed by Wong - Baker FACES rating scale.
Timepoint [2] 298949 0
This will be assessed at baseline before sirolimus treatment and at 3 monthly intervals.
Secondary outcome [1] 325134 0
MRI of the vascular anomalies will be performed pre-treatment, and every 6 months while the child is on sirolimus treatment (12 months) and until 1 year post end treatment
Size of the vascular anomaly will be monitored using MRI.
Timepoint [1] 325134 0
1-2 years
MRI of the vascular anomalies will be performed pretreatment, and every 6 months while the child is on sirolimus treatment (12 months) and until 1 year post end treatment.

Eligibility
Key inclusion criteria
Inclusion criteria include children in the age group of zero to eighteen years who have complex vascular anomalies. Examples include children with the following:
1. Venous Malformations with localised intravascular coagulopathy or severe pain failing to respond to sclerotherapy and /or surgery;
2. Lymphatic Malformations which compromise the airway or vision or are causing a low albumin level;
3. Newly diagnosed Kaposiform haemangioendothelioma/tufted angioma: in view of the promising data from the US on the use of sirolimus as initial treatment for KHE (1,2,5), sirolimus will be given to newly diagnosed patients and the results compared to our historical controls, namely children who had received vincristine as initial therapy.
4. Relapsed Kaposiform haemangioendothelioma: children who have previously been successfully treated with vincristine therapy and then have a recurrence of their tumour will be treated with sirolimus;
5. Generalised Lymphatic Anomalies with bone erosions, chylous leak or infiltration of lungs and gastrointestinal tract;
6. localised lymphatic anomalies not amenable to an operation;
7. Children with various overgrowth syndromes who have benign tumours, asymmetry, pain and coagulopathy that have failed usual therapeutic options and are causing significant symptoms
Minimum age
1 Days
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Children who are severely immunocompromised will be excluded from the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Single-centre prospective research study
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis
This is a drug trial on very rare and complex conditions. Hence the number in the study group won't be statistically significant

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 6028 0
Sydney Children's Hospital - Randwick
Recruitment postcode(s) [1] 13478 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 293925 0
Hospital
Name [1] 293925 0
Sydney Children's Hospital
Address [1] 293925 0
Sydney Children's Hospital
High Street
Randwick
NSW 2031
Country [1] 293925 0
Australia
Primary sponsor type
Hospital
Name
Sydney Children's Hospital, Randwick
Address
Sydney Children's Hospital, High Street, Randwick, NSW 2031
Country
Australia
Secondary sponsor category [1] 292748 0
None
Name [1] 292748 0
Address [1] 292748 0
Country [1] 292748 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295343 0
Sydney Childre's Hospital Network Human Research Ethics Committee
Ethics committee address [1] 295343 0
The Children's Hospital at Westmead
Locked Bag 4001
WESTMEAD
NSW 2145
Ethics committee country [1] 295343 0
Australia
Date submitted for ethics approval [1] 295343 0
04/07/2016
Approval date [1] 295343 0
28/02/2017
Ethics approval number [1] 295343 0

Summary
Brief summary
Why is this study important?
Vascular anomalies comprise a diverse group of diagnoses. The majority of these conditions are quite rare and have not been widely studied. Some of these lesions can impair vital structures, be deforming or even becoming life-threatening. Many children with complicated vascular anomalies have already failed the conventional treatment and are at risk of significant morbidity and mortality. Currently sirolimus is in clinical trials in various centres of Europe and United States of America. Case studies are suggestive of optimistic outcome.
By doing this prospective study, we will be able to assess the response and safety of this medication in our own patients which will definitely be a valuable contribution to the wider medical world to shine light on the management of this rare complex conditions .
The protocol is designed as a prospective research study. It involves children in the age group of Zero to Eighteen years. We envisage approximately 6 children per year for 5 years who have complex vascular anomalies will be deemed eligible for treatment with sirolimus. This includes children who are ineligible for or refractory to conventional treatments as well as children who are suffering from rare subtypes of vascular anomaly for whom there is no universally accepted standard therapy.
BACKGROUND INFORMATION
Vascular anomalies include a heterogeneous group of disorders that are categorized as vascular tumors or vascular malformations. The standard treatment options include resection, sclerotherapy and cytostatic chemotherapy. Some of these anomalies can be very complicated causing disfigurement, chronic pain and organ dysfunction with significant morbidity and mortality. These complicated vascular anomalies are quite rare and have not been widely studied. These patients have either failed the conventional treatment or unable to tolerate the available treatment due to life threatening side effects.
4 Supporting References from the review of literature
1) Adrienne M, MarySue W etal. Sirolimus for the treatment of complicated vascular anomalies in children. Paediatr Blood Cancer 2011;57:1018-1024.
2) Denise M, Cameron C etal. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics2016Feb 18:137(2):1-10.
3) Lackner H, Karastaneva A etal. Sirolimus for the treatment of children with various complicated vascular anomalies. Eur J Pediatr 2015 Dec; 174(12):1579-84.
4) Laurence M, Jennifer H etal. Rapamycin as novel treatment for refractory to standard care venous malformation. ISSVA 2016 Conference abst
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66958 0
A/Prof Orli Wargon
Address 66958 0
Department of Paediatric Dermatology
Sydney Children's Hospital
High Street
Randwick
NSW 2031
Country 66958 0
Australia
Phone 66958 0
+61419546959
Fax 66958 0
+61293829399
Email 66958 0
ORLI.WARGON@HEALTH.NSW.GOV.AU
Contact person for public queries
Name 66959 0
A/Prof Orli Wargon
Address 66959 0
Head of Department Dermatology
Sydney Children's Hospital
High Street
Randwick, NSW 2031
Country 66959 0
Australia
Phone 66959 0
+61293821776
Fax 66959 0
+61293820399
Email 66959 0
ORLI.WARGON@HEALTH.NSW.GOV.AU
Contact person for scientific queries
Name 66960 0
A/Prof Orli wargon
Address 66960 0
Head of Department Dermatology
Sydney Children's Hospital
High Street
Randwick, NSW 2031
Country 66960 0
Australia
Phone 66960 0
+61293821776
Fax 66960 0
+61293820399
Email 66960 0
ORLI.WARGON@HEALTH.NSW.GOV.AU

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results