UMIN-CTR Clinical Trial

Basic information
Public title	A multicenter, phase 3 study assessing efficacy and safety of the Sirolimus (Granules and Tablets) in the Treatment of intractable vascular anomalies
Acronym	Sirolimus for Intractable Vascular Anomalies(SIVA)
Scientific Title	A multicenter, phase 3 study assessing efficacy and safety of the Sirolimus (Granules and Tablets) in the Treatment of intractable vascular anomalies
Scientific Title:Acronym	Sirolimus for Intractable Vascular Anomalies(SIVA)
Region	Japan

Condition
Condition	Kaposiform hemangioendothelioma or Tufted angioma Lymphangioma (cystic lymphatic malformation), lymphangiomatosis (generalized lymphatic anomaly) or Gorham-Stout disease Venous malformation or blue rubber bleb nevus syndrome Complex-combined vascular malformations or Klippel-Trenanay-Weber syndrome
Classification by specialty	Hematology and clinical oncology Pediatrics
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	To assess efficacy and safety of mTOR inhibitor sirolimus granules and tablets in patients with intractable vascular anomalies
Basic objectives2	Efficacy
Basic objectives -Others
Trial characteristics_1	Confirmatory
Trial characteristics_2
Developmental phase	Phase III

Assessment
Primary outcomes	Target lesion response rate determined by Independent Review Facility after 24 weeks of treatments
Key secondary outcomes	Target lesion response rate determined by Independent Review Facility after 12 and 52 weeks of treatments Improvement of Skin lesion after 12, 24 and 52 weeks of treatments Evaluation of pleural effusion after 12, 24 and 52 weeks of treatments Evaluation of ascites after 12, 24 and 52 weeks of treatments Blood coagulation parameters after 12, 24 and 52 weeks of treatments Bleeding after 12, 24 and 52 weeks of treatments Pain after 12, 24 and 52 weeks of treatments QOL improvement rates after 12, 24 and 52 weeks of treatments ADL improvement rates after 12, 24 and 52 weeks of treatments Adverse events and side effects Laboratory values Vital signs Pharmacokinetics

Base
Study type	Interventional

Study design
Basic design	Single arm
Randomization	Non-randomized
Randomization unit
Blinding	Open -no one is blinded
Control	Uncontrolled
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms	1
Purpose of intervention	Treatment
Type of intervention	Medicine
Interventions/Control_1	An initial dose of sirolimus is single orally administered under fed or fasting condition. Subsequently, the sirolimus dosage is adjusted to achieve trough levels between 5-15 ng/mL.
Interventions/Control_2
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	1 months-old <=
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	1) Corrected aged 1 month or more at consent 2) Patients definitively diagnosed with the following diseases. Kaposiform hemangioendothelioma or Tufted angioma Lymphangioma (cystic lymphatic malformation), lymphangiomatosis (generalized lymphatic anomaly) or Gorham-Stout disease Venous malformation or blue rubber bleb nevus syndrome Complex-combined vascular malformations or Klippel-Trenanay-Weber syndrome 3) Patients having one or more measurable lesions evaluated by pretreatment MR imaging 4) Patients must have vascular anomalies that have potential to cause significant morbidity. 5) Normal liver, renal, and cardiac function at entry Total bilirubin < 3 x ULN for age CRE < 3 x ULN for age 6) Written consent to participate in this clinical trial has been given by the subject in person or by a legal guardian (when the subject is younger than 20 years at consent).
Key exclusion criteria	1) Past usage of mTOR inhibitors excluding sirolimus or other molecular target drugs relating mTOR pathway within 8 weeks 2) Patients who currently have an uncontrolled infection 3) Karnofsky Performance Status (PS) <= 30 (10 years of age) or Lansky play PS <= 30 (< 10 years of age) 4) Interstitial lung disease, uncontrolled diabetes, uncontrolled hypertension, uncontrolled hyperlipidemia, chronic liver disease, or chronic renal disease 5) Chronic treatment (>= 4 weeks) with systemic steroids or another immunosuppressive agent at entry. Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. 6) History of allergy to sirolimus, or additive substance 7) Patients must also avoid strong inducers of CYP3A4, and may not have received these medications within 1 week of entry. 8) Known history of HIV seropositivity or known immunodeficiency 9) Hepatitis B virus carrier and/or Hepatitis C virus carrier 10) Malabsorption of sirolimus 11) Patients who have undergone surgical resection or interventional radiology procedures for target lesions within 2 weeks 12) Patients who have received therapeutic medication for a target disease within 2 weeks 13) Patients who have received chemotherapy drugs that cause bone marrow suppression, biological drug, or off-label products within 4 weeks 14) Patients who have received radiation therapy for target lesions within 24 weeks 15) Patients who have participated another clinical trial within 4 weeks 16) Patients who have dental braces or prosthesis only if it interferes with radiologic analysis of lymphatic anomaly 17) Pregnant, probably pregnant, or breast-feeding woman. Patients or their partners who do not agree birth control during clinical trial. 18) Patients who have participated in clinical trial of sirolimus in the past. 19) Patient who is judged inappropriate to participate in this study by the investigators
Target sample size	10

Research contact person
Name of lead principal investigator	1st name Michio Middle name Last name Ozeki
Organization	Gifu University Hospital
Division name	Pediatrics
Zip code	501-1194
Address	1-1 Yanagido, Gifu City 501-1194, Japan
TEL	058-230-6000
Email	michioo@gifu-u.ac.jp

Public contact
Name of contact person	1st name Michio Middle name Last name Ozeki
Organization	Gifu University Hospital
Division name	Pediatrics
Zip code	501-1194
Address	1-1 Yanagido, Gifu City 501-1194, Japan
TEL	058-230-6000
Homepage URL
Email	michioo@gifu-u.ac.jp

Sponsor
Institute	Gifu University Hospital
Institute
Department

Funding Source
Organization	AMED
Organization
Division
Category of Funding Organization	Japanese Governmental office
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Gifu University Hospital IRB
Address	1-1 Yanagido, Gifu City 501-1194, Japan
Tel	058-230-6000
Email	chikenj@gifu-u.ac.jp

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information	2019 Year 12 Month 25 Day

Related information
URL releasing protocol
Publication of results	Unpublished

Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	No longer recruiting
Date of protocol fixation	2019 Year 09 Month 06 Day
Date of IRB	2019 Year 11 Month 14 Day
Anticipated trial start date	2020 Year 01 Month 06 Day
Last follow-up date	2022 Year 02 Month 28 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other
Other related information

Management information
Registered date	2019 Year 12 Month 24 Day
Last modified on	2021 Year 03 Month 02 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000044448