Clinical Trials Register

Summary
EudraCT Number:	2015-001703-32
Sponsor's Protocol Code Number:	VASE
National Competent Authority:	Norway - NOMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-11-28
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Norway - NOMA

A.2

EudraCT number

2015-001703-32

A.3

Full title of the trial

Phase III multicentric study evaluating the efficacy and safety of sirolimus in Vascular Anomalies that are refractory to standard care.

Fase 3 multisenter studie for evaluering av behandlingseffekt og bivirkninger av sirolimus mot blodåremisdannelser som ikke bedres på standard behandling

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Effects and treatment effect of sirolimus used against blood vessel deformities that are not suitable for surgical or other established treatment, or where established treatment has proven not to give satisfactory results

Virkninger og behandlingseffekt av sirolimus brukt mot blodåremisdannelser som ikke er egnet for kirurgisk eller annen etablert behandling, eller hvor etablert behandling har vist seg ikke å gi tilfredstillende resultat

A.3.2

Name or abbreviated title of the trial where available

VASE

A.4.1

Sponsor's protocol code number

VASE

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02638389

A.5.4

Other Identifiers

Name:

2018/1897

Number:

Regional etisk kommitè sør-øst D

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Cliniques Universitaires Saint-Luc (CUSL)
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Limited
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cliniques Universitaires Saint-Luc (CUSL)
B.5.2	Functional name of contact point	Center for Vascular Anomalies
B.5.3	Address:
B.5.3.1	Street Address	Avenue Hippocrate, 10
B.5.3.2	Town/ city	Bruxelles
B.5.3.3	Post code	1200
B.5.3.4	Country	Belgium
B.5.4	Telephone number	3227641403
B.5.5	Fax number	3227647460
B.5.6	E-mail	laurence.boon@uclouvain.be

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Rapamune
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Rapamune
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Complex vascular anomalies causing debilitating functional and esthetic impairment that are resistant to standard care

Komplekse blodåremisddannelser som medfører betydelig redusert funksjon og estetiske plager og som samtidig ikke responderer på eller er tilgjengelig for standard tilgjengelig behandling

E.1.1.1

Medical condition in easily understood language

Complex vascular anomalies

Komplekse blodåremisdannelser

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	HLT
E.1.2	Classification code	10047047
E.1.2	Term	Vascular anomalies congenital NEC
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objectives of this prospective multicentric study are to assess the potential Statistical efficacy and side effects of the drug:
- whether sirolimus treatment can alleviate signs and symptoms caused by these complex vascular anomalies that are refractory to standard care
- whether patients With this rare disorder will see their quality of life improved
- whether this treatment can statistically reduce the anemia and coagulation abnormalities observed in some patients With venous anomalies.
- monitor and report systematically on side effects of sirolimus when given to this Group of patients and at the given dose

Hovedmålene med denne prospektive multisenterstudien er å vurdere den potensielle effekten av medikamentet:

- om sirolimus-behandling kan lindre tegn og symptomer forårsaket av disse komplekse vaskulære misdannelsene som ikke responderer eller lar seg behandle med dagens standard metoder.

- om pasienter med denne sjeldne lidelsen vil se sin livskvalitet forbedret med sirolimusbehandling

- om denne behandlingen statistisk kan redusere anemi og koagulationsforstyrrelser observert hos noen pasienter med venøse anomalier.

-registrere og rapportere systematisk på bivirkninger av sirolimus hos pasienter med vaskulære malformasjoner

E.2.2

Secondary objectives of the trial

-to confirm the safety of this treatment
-to see which patients would benefit the most, and thus indicated for rapamycin in the future
-to assess whether sirolimus could reduce volume of the malformation (on MRI) on a long-term follow-up

- å bekrefte sikkerheten ved denne behandlingen
- å se hvilke pasienter som vil ha mest nytte av behandlingen og dermed indikere for bruk av rapamycin i fremtiden
- å vurdere om sirolimus kan redusere volumet av misdannelsene (vurdert på MR) ved en langtidsoppfølging

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion is limited to children and adults from 1 year* to 70 years ( in Norway).
* In Belgium, the Netherlands and France 3 months to 70 years. In Germany 18 to 70 years.

-Patients with complex vascular anomalies that are refractory to standard care such as medical treatment, surgical resection and/or sclerotherapy/embolization (ineffective or accompanied by major complications) --ref page 57: Clinical parameters / diagnosis: Given the lack of response to conventional treatment (compression stockings, anti-pain, low molecular weight heparin, sclerotherapy and/ or surgery) (Dompmartin et al Phlebology 2010)

-Patients must have adequate bone marrow function: Hemoglobine> 10,0 g/dl, neutrophils >1500/mm³ and platelets > 100.000/mm³

Patients must have the following laboratory values:
-Total serum bilirubin ≤ 1.5 x ULN (Upper Limit Normal) or totally bilirubin ≤3 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with well documented Gilbert Syndrome
--Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or <5.0 x ULN if hepatic metastases are present)
-Serum creatinine ≤ 1.5 x ULN. If the serum creatinine is ≥ 1.5 x ULN, then a 24-hour Creatinine Clearance must be conducted and the result must be ≥ 60 mL/min.

- Karnofsky score > 50
- Patients have to be able to sign the informed consent
- For children, parents or legal relatives have to be able to sign the informed consent
- Women in age of reproduction have to be informed that contraceptive methods are mandatory during the study time

Inklusjon er begrenset til barn og voksne fra 1 år * til 70 år (i Norge).
* I Belgia, Nederland og Frankrike 3 måneder til 70 år. I Tyskland 18 til 70 år.
-Pasienter med komplekse vaskulære anomalier som ikke responderer tilstrekkelig på eller ikke er egnet for standard behandling som medisinsk behandling, kirurgisk reseksjon og / eller skleroterapi / embolisering (ineffektiv eller ledsaget av store komplikasjoner eller stor sannsynlighet for store komplikasjoner)--ref side 57: Kliniske parametere / diagnose: Gitt mangelen på respons på konvensjonell behandling (kompresjonsstrømper, antismerter, lavmolekylær heparin, skleroterapi og / eller kirurgi) (Dompmartin et al Phlebology 2010)

- Pasienter må ha tilstrekkelig beinmargsfunksjon: Hemoglobin> 10,0 g / dl, nøytrofiler> 1500 / mm³ og blodplater > 100.000 / mm³

- Pasienter må ellers ha følgende laboratorieverdier:
- Totalt serumbilirubin ≤ 1,5 x ULN (Upper Limit Normal) eller totalt bilirubin ≤3 x ULN med direkte bilirubin ≤ 1,5 x ULN hos pasienter med godt dokumentert Gilbert-syndrom

- Serum alanin aminotransferase (ALAT) og aspartat aminotransferase (ASAT) ≤ 3 x ULN (eller <5,0 x ULN hvis levermetastaser er til stede)
- Serumkreatinin 1,5 x ULN. Hvis serumkreatinin er ≥ 1,5 x ULN, må en 24-timers kreatininclearance utføres, og resultatet må være ≥ 60 ml / min.
- Karnofsky score > 50
- Pasienter må kunne signere det informerte samtykket
- For barn ¨må foreldre eller juridisk verge være i stand til å signere informert samtykkeskjema.
- Kvinner i fertil alder må informeres om at sikker prevensjonsmetode er obligatorisk i studietiden

E.4

Principal exclusion criteria

Any of the following concurrent severe and/or uncontrolled medical conditions, which could compromise participation in the study or interfere with the study results:

•Impaired cardiac function or clinically significant cardiac diseases, including unstable angina pectoris, ventricular arrhythmia, valvular disease with documented compromise in cardiac function, myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function, history of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy, family history of congenital long or short QT, or known history of QT/QTc prolongation of Torsades de Pointes (TdP)

-Impairment of Gastro-Intestinal (GI) function or GI disease that may significantly alter the absorption of sirolimus (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea ≥ Grade 2, malabsorption syndrome, or small bowel resection)

- 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, including history of non-melanoma skin cancer, but With the exception of carcinoma in situ of cervix.

- Immunocompromised patients, including known seropositivity for HIV
- Pregnant or lactating women
- Prior treatment with PI3K and/or mTOR inhibitors

Samtlige av følgende samtidige alvorlige og / eller ukontrollerte medisinske tilstander, som kan kompromittere deltakelse i studien eller forstyrre studieresultatene:

• Nedsatt hjertefunksjon eller klinisk signifikante hjertesykdommer, inkludert ustabil angina pectoris, ventrikulær arytmi, valvulær sykdom med dokumentert kompromiss i hjertefunksjon, hjerteinfarkt i løpet av de siste 6 månedene, dokumentert av vedvarende forhøyede hjerteenzymer eller vedvarende regionale veggavvik ved vurdering av LVEF funksjon, historie med dokumentert kongestiv hjertesvikt (New York Heart Association funksjonell klassifisering III-IV), dokumentert kardiomyopati, familiehistorie med medfødt lang eller kort QT, eller kjent historie med QT / QTc forlengelse av Torsades de Pointes (TdP)

- Nedsatt funksjon av gastrointestinal (GI) eller GI sykdom som kan endre absorpsjonen av sirolimus betydelig (f.eks. Ulcerøs sykdom, ukontrollert kvalme, oppkast, diaré ≥ grad 2, malabsorpsjonssyndrom eller tarmtarm reseksjon)

- Kjent overfølsomhet for medisiner eller metabolitter fra lignende klasser som studiebehandling.
- Pasienten har annen samtidig alvorlig og / eller ukontrollert medisinsk tilstand som etter forskerens vurdering ville kontraindisert deltakelse i den kliniske studien (f.eks. Akutt eller kronisk pankreatitt, levercirrhose, aktiv kronisk hepatitt, alvorlig nedsatt lungefunksjon med en spirometri ≤ 50% av den normale predikerte verdien og / eller O2-metning ≤ 88% i ro osv.)

- Nyere historie med primær malignitet ≤ 5 år, inkludert historie med hudkreft som ikke er melanom, men med unntak av karsinom i livmorhalsen.

- Immunkompromitterte pasienter, inkludert kjent seropositivitet for HIV
- Gravide eller ammende kvinner
- Før behandling med PI3K- og / eller mTOR-hemmereRecent

E.5 End points

E.5.1

Primary end point(s)

Primary End Point (repeat as necessary) : to assess the potential statistical efficacy of the drug:
- whether sirolimus treatment can alleviate signs and symptoms caused by these complex vascular anomalies that are refractory to standard care
- whether patients with this rare disorder will see their quality of life improved.
- whether this treatment can statistically reduce the anemia and coagulation abnormalities observed in some patients with venous anomalies.

Primært endepunkt for å vurdere den potensielle statistiske effekten av stoffet:

- om sirolimusbehandling kan lindre tegn og symptomer forårsaket av disse komplekse blodåremisdannelsene som viser seg ikke å respondere på tilgjengelig standard behandling
- om pasienter med denne sjeldne lidelsen vil se sin livskvalitet forbedret under sirolimusbehandling.
- om denne behandlingen statistisk kan redusere anemi og koagulasjonsforstyrrelser observert hos noen pasienter med venøse anomalier.

E.5.1.1

Timepoint(s) of evaluation of this end point

Every month for the first 3 months and then every 3 months during the treatment period (2 years). The patient will be followed-up during a total of 5 years (evaluation will be performed every three month during the first 2 years and then every 6 months).

Hver måned de første 3 månedene og deretter hver tredje måned i behandlingsperioden (2 år). Pasienten vil bli fulgt opp i totalt 5 år (evaluering vil bli utført hver tredje måned i løpet av de første 2 årene og deretter hver 6. måned).

E.5.2

Secondary end point(s)

- to confirm the safety of this treatment
- to see which patients would benefit the most, and thus indicated for rapamycin in the future
- to assess whether sirolimus could reduce volume of the malformation (on MRI) on a long-term follow-up

- å bekrefte sikkerheten ved denne behandlingen
- å se hvilke pasienter som ville ha mest nytte av behandlingen, og dermed indikere for hvem som primært bør få rapamycin i fremtiden
- å vurdere om sirolimus kan redusere volumet av misdannelsen (vurdert ved MR) ved langtidsoppfølging

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Patient before and during the trial and on / off medication. Historic control.

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Siste besøk siste pasient

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

160

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

250

F.4.2.2

In the whole clinical trial

250

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Continue with this medication if the efficacy has been proven and the drug is accepted and tolerated by the patient. Alternatively try newly identified medication that would give better results on the basis of better understanding of the etiopathogenic mechanisms underlying the disorders

Fortsette med denne medisinen hvis god effekt er påvist og den tåles godt av pasienten. Alternativt prøve nyidentifiserte medisiner som forventes å gi bedre resultater på basis av en bedret forståelse av de etiologiske og patologiske mekanismene som forårsaker lidelsen

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-05-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-12-12

P. End of Trial
P.	End of Trial Status	Ongoing

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