Clinical Trials Register

Summary
EudraCT Number:	2015-001096-43
Sponsor's Protocol Code Number:	PHRN14-AM/PERFORMUS
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-07-23
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

France - ANSM

A.2

EudraCT number

2015-001096-43

A.3

Full title of the trial

Treatment of superficial voluminous complicated slow-flow vascular malformations with sirolimus: a phase 2 trial in children
observational-phase designed

A.3.1

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

suPERficial slow-flow vascular malFORMations treated with sirolimUS

A.3.2

Name or abbreviated title of the trial where available

PERFORMUS

A.4.1

Sponsor's protocol code number

PHRN14-AM/PERFORMUS

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	CHRU de Tours
B.1.3.4	Country	France
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	Direction Générale de l'Offre des Soins
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHRU de Tours
B.5.2	Functional name of contact point	Clinical Resaerch Associate
B.5.3	Address:
B.5.3.1	Street Address	Direction des Affaires Médicales, 2 bd tonnellé
B.5.3.2	Town/ city	Tours
B.5.3.3	Post code	37044
B.5.3.4	Country	France
B.5.4	Telephone number	+33247474638
B.5.5	Fax number	+33247474662
B.5.6	E-mail	aurelie.darmaillacq@univ-tours.fr

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
D.2.1.2	Country which granted the Marketing Authorisation	France
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SIROLIMUS
D.3.9.1	CAS number	53123-88-9
D.3.9.4	EV Substance Code	SUB10537MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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)	No
	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)	No
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
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SIROLIMUS
D.3.9.1	CAS number	53123-88-9
D.3.9.4	EV Substance Code	SUB10537MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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)	No
	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)	No
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: 3
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
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SIROLIMUS
D.3.9.1	CAS number	53123-88-9
D.3.9.4	EV Substance Code	SUB10537MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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)	No
	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)	No
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

vascular malformations

E.1.1.1

Medical condition in easily understood language

vascular malformations

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10074979
E.1.2	Term	Vascular malformation
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess whether a treatment with mTOR inhibitor sirolimus induces a reduction in volume of voluminous slow-flow superficial vascular malformations of children evaluated on MRI, at the end of a treatment period ranging from 4 to 8 months, as compared to an observational period (also during between 4 to 8 months)

E.2.2

Secondary objectives of the trial

1. To evaluate the efficacy of study treatment by:
-Qualitative assessment of efficacy on digital photographs
-Patient self assessment or parents self assessements on
o Global assessment
o Reduction of cutaneous skin complications/symptoms (seepage, bleeding, skin tension, functional impairment)
o Reduction of pain
o Improvement of quality of life
-Dermatologist’s global assessement of efficacy
-Decrease of VEGF and TF plasma levels
-Normalisation of platelet count, and fibrinogen, D-dimers, factor V levels
2. To evaluate safety of sirolimus treatment on children with a voluminous slow-flow VM
3. To carry out an organic collection of skin and blood samples, in order to perform current and further genetic analysis of several genes involved in vasculogenesis and involved in VMs, especially TIE2 and PIK3CA.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

* Patients aged from 6 years to 18 years (when submitting the intention letter, we aimed to include children from 12 months to 18 years. The minimal age was changed in the current protocol to children up to 6 years, because our protocol requires repeated MRI, which is non invasive imaging but requires sedation under the age of 5-6 years. We thus found too invasive to perform repeated sedations in toddlers)
* With a slow-flow VM confirmed by MRI, included or not into a genetic disorder, among the following:
- microcystic lymphatic malformation
- mixed micro- and macrocystic malformation
- venous malformation
- combined lymphatic and venous malformation
* Malformation voluminous (defined as ≥ 5 % of body surface) and complicated (pain, functional impairment, bleeding, seepage)
* Extended to the underlying subcutaneous tissue, to the fascias, the muscles and/or the underlying bone
* MRI of the VM performed within 8 months
* Vaccination schedule updated
* Informed, written consent of the subject’s parents or the 18 years old subject (see §9.3 Screening and baseline visits)
* Cooperative parent or subject, aware of the necessity and duration of controls so that perfect adhesion to the protocol could be expected
* Subjects or subject’s parents covered by or having the rights to social security

E.4

Principal exclusion criteria

Non Inclusion criteria linked to the condition
 Slow-flow VMs which are only macrocystic lymphatic malformations
 Visceral life-threatening involvement
Non inclusion criteria linked to sirolimus
 Patients who received prior per os treatment with an mTOR inhibitor
 Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
 Known chronic infectious disease
 History of cancer in the 2 previous years
 Brest feeding or pregnant women, or women on childbearing age without effective contraception, up to 12 weeks after treatment discontinuation
 Known allergy to mTOR inhibitor
 Concomitant treatment that inhibits or activates CYP3A4, and P-gp glycoprotein, cytotoxic drugs, antilymphocyte immunoglobulines and metoclopramide
 Intolerance to fructose, intolerance or malabsorption to glucose, galactose, metabolic insufficiency in sucrase-isomaltase, metabolic defect in lactase
 Known allergy to peanuts or soyabean
 Liver insufficiency (elevated transaminases > 2.5 N)
 Anemia with Hb < 9 g/dl
 Leukopenia < 1000/mm3
 Thrombocytopenia < 80 000/mm3
 Hypercholesterolemia (LDL-cholesterol ≥ 2g/l)
 Patients with risk of opportunistic infections
 Live attenuated vaccine up to 3 months after sirolimus discontinuation
Other non inclusion criteria
 Contraindication of MRI
 Known allergy to lidocaïne (only for patients who accept genetic analysis1)
 Subject already participating to a therapeutic study

E.5 End points

E.5.1

Primary end point(s)

Primary outcome will be based on the volume of the VMs on MRI. Three MRI will be performed: one at baseline (M0) for diagnosis of the VM (routine care), one at the date of switch from the observational period to the sirolimus period (MS) and one at the end of follow-up (M12). Relative change of volume, standardized by the duration period, will define the outcome. Thus, for the observational period, the primary outcome is defined as {(VMS – V0)/V0}/(MS-M0) where V0 and VMS are the volumes assessed at baseline and month S, respectively, and (MS-M0) corresponds to the duration of the observational period. For the sirolimus period, the outcome is defined in the same way as {(V12 – VMS)/VMS}/(M12-MS), where V12 is the volume assessed at month 12 and (M12-MS) corresponds to the duration of the sirolimus period.
Interpretation of the MRI will be centralized and performed by a radiologist blinded from physical assessment and from treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 month

E.5.2

Secondary end point(s)

- Qualitative assessment of efficacy on digital photographs, by two blinded independent readers. For each patient, readers will be provided the baseline photograph. Then they will be provided the three other photographs (realized at visit v2, v3 and at the last visit) and will be asked to identify which photograph was performed at the end of the observational period, and which was performed at the end of the sirolimus period. Such a procedure comes down to a “Lady-tasting-tea” procedure (Falissard et al. International Journal of Statistics in Medical Research 2013;2:88-93).
- Patient self assessment or parents self assessements :
o Global treatment efficacy on a visual analogic scale (0-10)
o Skin complications/symptoms (seepage, bleeding, skin tension, functional impairment)
o Pain on a visual analogic scale (0-10)
o Quality of life by the dermatological quality of life scale (DLQI adapted to children)
- Dermatologist’s global assessement of efficacy on a visual analogic scale (0-10)
- VEGF and TF plasma levels
- Platelet count, and fibrinogen, D-dimers, factor V levels supporting the presence and disappearance of an abnormal intravascular coagulation consumption
For the latter outcomes, as for the primary outcome, relative change over the observational and sirolimus period will be considered, and standardized by the period durations.
- Adverse events and safe adverse events
- From the organic collection (including blood and skin samples) analysis of several genes involved in vasculogenesis (currently TIE2 and PIK3CA) will be performed. A genotype/phenotype study will be carried out.

E.5.2.1

Timepoint(s) of evaluation of this end point

12 month

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

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

Yes

E.8.1.7.1

Other trial design description

randomized observational-phase design

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

each patient will be his/her own 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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Yes

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

The end of the trial is the last visit of the last subject undergoing the trial

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

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)

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:

F.1.3

Elderly (>=65 years)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

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)

After the end of the protocol, sirolimus might be maintained, at the discretion of investigators.

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

2015-07-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-03-23

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