Clinical Trials Register

Summary
EudraCT Number:	2010-019519-39
Sponsor's Protocol Code Number:	RAPIT
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2011-12-01
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

Netherlands - Competent Authority

A.2

EudraCT number

2010-019519-39

A.3

Full title of the trial

Efficacy of RAD001/everolimus in Autism and NeuroPsychological deficits in children with TSC (RAPIT-trial)

Onderzoek naar behandeling van leer- en gedragsproblemen bij kinderen met Tubereuze Sclerose Complex met RAD001

A.3.1

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

Efficacy of RAD001/everolimus in Autism and NeuroPsychological deficits in children with tuberous sclerosis complex (RAPIT-trial)

Onderzoek naar behandeling van leer- en gedragsproblemen bij kinderen met Tubereuze Sclerose Complex met RAD001

A.3.2

Name or abbreviated title of the trial where available

RAPIT

A.4.1

Sponsor's protocol code number

RAPIT

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	Erasmus MC - Department of Neurology
B.1.3.4	Country	Netherlands
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	Sophia Stichting Wetenschappelijk Onderzoek
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Hersenstichting
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus MC
B.5.2	Functional name of contact point	Clinical trials information
B.5.3	Address:
B.5.3.1	Street Address	Dr. Molewaterplein 60
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015 GE
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31107036595
B.5.5	Fax number	+31107036345
B.5.6	E-mail	m.c.y.dewit@erasmusmc.nl

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	Votubia
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/764
D.3 Description of the IMP
D.3.1	Product name	Everolimus
D.3.2	Product code	L04AA18
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Votubia
D.3.9.1	CAS number	159351-69-6
D.3.9.3	Other descriptive name	EVEROLIMUS
D.3.9.4	EV Substance Code	SUB02065MIG
D.3.10	Strength
D.3.10.1	Concentration unit	ng nanogram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 15
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Tuberous Sclerosis Complex

E.1.1.1

Medical condition in easily understood language

TSC is a genetic disease that leads to intellectual disability in over 50% of patients, and to learning problems, behavioral problems, autism and epilepsy in up to 90% of patients.

E.1.1.2

Therapeutic area

Body processes [G] - Genetic Phenomena [G05]

MedDRA Classification

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 objective is to determine the effect of Everolimus on the cognition of children with TSC, measured by
IQ.

E.2.2

Secondary objectives of the trial

We will also evaluate the effect on symptoms of autism spectrum disorder, other (neuro) psychological test parameters, seizure frequency, EEG-abnormalities and specific symptoms of learning disability. Furthermore, we will observe the tolerability of Everolimus in children with TSC.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Title: RAPIT-MRI
Date: 16-08-2012
Version: 1
Objective: Magnetic resonance imaging (MRI) of the brain will be made for each participant of the RAPIT trial before and after trial participation. This way, the effect of the investigational drug on the structural abnormalities in the brain can be assessed, and related to cognitive performance.
Primary outcome will be white matter integrity (DWI/DTI), volume of (sub)cortical tubers, subependymal nodules (SEN) and subependymal giant-cell astrocytomas (SEGA).
Secondary outcome will be the correlation between structural brain changes and changes in neuropsychological functioning.
This study is a substudy of the RAPIT trial. Participants of the RAPIT trial will get the choice to have the MRI before and after trial participation. If participant and/or his/her parents do not want to have the MRI, the participant can still enter the RAPIT trial.

E.3

Principal inclusion criteria

• Children with a definite diagnosis of TSC between 3 and 18 years.
• With an IQ estimated <80 and/or special schooling and/or autism spectrum disorder and/or learning disability
requiring remedial teaching.
• Written informed consent by parents/care-takers, and the patient if he or she is 12 years or older and cognitively
able to consent.
• In girls after menarche, appropriate contraception must be used or abstinence practiced.

E.4

Principal exclusion criteria

• Renal or liver dysfunction
• Surgery <6wk before entering the study
• Current infection at time of inclusion
• Additional diseases or disorders that may influence the endpoints
• Allergy for any of the components of the study medication

E.5 End points

E.5.1

Primary end point(s)

Cognitive functioning: Mullen scales (IQ)

E.5.1.1

Timepoint(s) of evaluation of this end point

IQ measurements will be obtained at inclusion and at the last study visit.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

All tests will be executed at inclusion and at the last study visit.

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3

Other

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

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 trial ends when the last patient has completed 12 months of treatment and all tests of the last visit are done.
For details see protocol.

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)

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

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2011-12-01.

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children aged >12 years that might have developmental delay.

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 trial, patients will continue their normal treatment as they did during the trial, because the study medication will be given on top of the standard care. If it turns out everolimus has multiple benefits for the patients, a follow-up trial will be started to follow patients that want to start everolimus again.

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

2011-12-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-03-14

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

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