ANZCTR - Registration

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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]

Nil Known

Secondary ID [2]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Complex vascular malformations

Complex lymphatic malformations

Vascular tumours (tufted angiomas and kaposiform haemangioendotheliomas)

Generalised lymphatic anomalies

PIKC3A related overgrowth syndrome (PROS)

Condition category

Condition code

Cardiovascular

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]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

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]

Pain will be assesed by Wong - Baker FACES rating scale.

Timepoint [2]

This will be assessed at baseline before sirolimus treatment and at 3 monthly intervals.

Secondary outcome [1]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/08/2016

Actual

31/03/2017

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]

Sydney Children's Hospital - Randwick

Recruitment postcode(s) [1]

2031 - Randwick

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Sydney Children's Hospital

Address [1]

Sydney Children's Hospital
High Street
Randwick
NSW 2031

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sydney Childre's Hospital Network Human Research Ethics Committee

Ethics committee address [1]

The Children's Hospital at Westmead
Locked Bag 4001
WESTMEAD 
NSW 2145

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

04/07/2016

Approval date [1]

28/02/2017

Ethics approval number [1]

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

A/Prof Orli Wargon

Address

Department of Paediatric Dermatology
Sydney Children's Hospital
High Street
Randwick
NSW 2031

Country

Australia

Phone

+61419546959

Fax

+61293829399

ORLI.WARGON@HEALTH.NSW.GOV.AU

Contact person for public queries

Name

Orli Wargon

Address

Head of Department Dermatology
Sydney Children's Hospital
High Street
Randwick, NSW 2031

Country

Australia

Phone

+61293821776

Fax

+61293820399

ORLI.WARGON@HEALTH.NSW.GOV.AU

Contact person for scientific queries

Name

Orli wargon

Address

Head of Department Dermatology
Sydney Children's Hospital
High Street
Randwick, NSW 2031

Country

Australia

Phone

+61293821776

Fax

+61293820399

ORLI.WARGON@HEALTH.NSW.GOV.AU

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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