Clinical Trials Register

Summary
EudraCT Number:	2016-005022-10
Sponsor's Protocol Code Number:	SYN-1748-MAL-0030-I
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-11-09
Trial results	View 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

Germany - BfArM

A.2

EudraCT number

2016-005022-10

A.3

Full title of the trial

Improvement of synaptic plasticity and cognitive function in RAS pathway disorders

Verbesserung der synaptischen Plastizität und kognitiven Funktionen bei Patienten mit Erkrankungen des RAS Signalweges

A.3.1

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

Improvement of synaptic plasticity and cognitive function in RAS pathway disorders

Verbesserung der synaptischen Plastizität und kognitiven Funktionen bei Patienten mit Erkrankungen des RAS Signalweges

A.4.1

Sponsor's protocol code number

SYN-1748-MAL-0030-I

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	Technische Universität München, Fakultät für Medizin
B.1.3.4	Country	Germany
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	BMBF DLR Projektträger Grant Number: 01 GM1519C
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Technische Universität München
B.5.2	Functional name of contact point	Lehrstuhl für Sozialpädiatrie
B.5.3	Address:
B.5.3.1	Street Address	Heiglhofstraße 65
B.5.3.2	Town/ city	München
B.5.3.3	Post code	81377
B.5.3.4	Country	Germany
B.5.4	Telephone number	00498971009236
B.5.5	Fax number	00498971009253
B.5.6	E-mail	nikolai.jung@tum.de

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	No
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.1	Product name	Lovastatin
D.3.4	Pharmaceutical form	Capsule, hard
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	Lovastatin
D.3.9.1	CAS number	75330-75-5
D.3.9.3	Other descriptive name	LOVASTATIN
D.3.9.4	EV Substance Code	SUB08604MIG
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	50
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	Yes
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	No
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.1	Product name	Lamotrigin beta
D.3.4	Pharmaceutical form	Capsule, hard
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	Lamotrigin
D.3.9.1	CAS number	84057-84-1
D.3.9.4	EV Substance Code	SUB08393MIG
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	300
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	Yes
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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
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

Noonan Syndrom and Neurofibromatosis Type 1

Noonan Syndrom und Neurofibromatosis Type 1

E.1.1.1

Medical condition in easily understood language

Noonan Syndrom and Neurofibromatosis Type 1

Noonan Syndrom und Neurofibromatosis Type 1 (Erbkrankheiten)

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10029748
E.1.2	Term	Noonan syndrome
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10029268
E.1.2	Term	Neurofibromatosis
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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

Primary Objective:
Does the pharmacological intervention with (a) Lovastatin and (b) Lamotrigine improve synaptic plasticity in patients with Noonan syndrome and neurofibromatosis type 1.

Primäres Ziel:
Führen (a) Lovastatin und (b) Lamotrigin zu einer Verbesserung bzw. Normalisierung der synaptischen Plastizität bei Patienten mit Noonan Syndrom und Neurofibromatose Typ I

E.2.2

Secondary objectives of the trial

Secondary Objective:
Does the pharmacological intervention with (a) Lovastatin and (b) Lamotrigine improve attentional performance measured by the Test for Attentional Performance (TAP) in patients with Noonan syndrome and neurofibromatosis type 1.

Nebenziel:
Führt die Einnahme von (a) Lovastatin und (b) Lamotrigin zu einer Verbesserung der Kognition/Aufmerksamkeit bei Patienten mit Noonan Syndrom und Neurofibromatose Typ I

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. 1. Group 1: NS, Group 2: NF1 (both genetically assured)
2. Age ≥16 years
3. The adolescent (≥16) and legal guardian who are capable to give their consent and understand the aim and rationale of the study. In case of doubts, an independent medical practitioner will evaluate the capacity to consent.
4. Signed informed consent if ≥ 16 years and legal guardian.
5. Persons who are ≥ 18 years old and capable to give their consent and understand the aim and rationale of the study. In case of doubts, an independent medical practitioner will evaluate the capacity to consent.
6. Signed informed consent if ≥ 18 years.
7. Male participants and female participants who are not capable of bearing children or who use a method of contraception that is medically approved by the health authority of the respective country.
This includes:
- A woman who is not capable of bearing a child is defined as follows: post-menopausal (12 months natural (spontaneous) amenorrhea or 6 months spontaneous amenorrhea with serum-FSH-values (follicle-stimulating hormone) of >40 mIU/mL); 6 weeks after a bilateral ovariectomy with or without hysterectomy or sterilization by means of tubal ligation
- A woman capable of bearing child is defined as follows: a woman who is physiologically capable of becoming pregnant, including women whose occupation, lifestyle or sexual orientation exclude sexual intercourse with a male partner and women whose partners have been sterilized by vasectomy or other measures.
- Medically-approved methods of contraception can include the following: hormonal contraceptives, intrauterine device and double barrier method. Acceptable preventive measures can include total abstinence at the discretion of the investigator, in cases where compliance is ensured because of the study participant’s age, occupation, lifestyle or sexual orientation. Periodical abstinence (e.g. calendar, ovulation, symptothermal methods or abstinence until the 4th day after the ovulation) as well as coitus interruptus are not acceptable methods of contraception.
- A reliable method of contraception must be used for the entire duration of the study.
The dosage of oral contraceptives has to be doubled during the study period or two different methods of contraception should be combined.

1. 2. 1. Gruppe 1: NS; Gruppe 2 NF1 (beide Syndrome genetisch bestätigt):
2. Alter ≥ 16 Jahre
3. Jugendliche (≥ 16) und Erziehungsberechtigte, die in der Lage sind, ihre Zustimmung zu geben und das Ziel und den Zweck der Studie zu verstehen. Im Zweifelsfall beurteilt ein unabhängiger Arzt die Einwilligungsfähigkeit.
4. Unterzeichnete Einverständniserklärung, ≥ 18 Jahre.
5. Unterzeichnete Einverständniserklärung, ≥ 16 Jahre und dem Erziehungsberechtigten.
6. Patienten (≥ 18) die in der Lage sind, ihre Zustimmung zu geben und das Ziel und den Zweck der Studie zu verstehen. Im Zweifelsfall beurteilt ein unabhängiger Arzt die Einwilligungsfähigkeit.
7. Männliche Teilnehmer und weibliche Teilnehmer, die keine Kinder gebären können oder die eine Verhütungsmethode nutzen, die medizinisch / ärztlich durch die Gesundheitsbehörde des jeweiligen Landes anerkannt ist.
Dies schliesst ein:
 Eine Frau, die keine Kinder gebären kann ist folgendermaßen definiert: postmenopausal (12 Monate natürliche (spontane) Amenorrhö oder 6 Monate spontane Amenorrhö mit Serum-FSH Werten (Follikel-stimulierendes Hormon) >40 mlU/ml); 6 Wochen nach beidseitiger Ovarektomie mit oder ohne Hysterektomie oder Sterilisation durch Tubenligatur.
 Eine Frau, die Kinder gebären kann, ist folgendermaßen definiert: Frauen, die physiologischerweise schwanger werden können. Dies schließt Frauen mit ein, deren Arbeit, Lebensstil oder sexuelle Orientierung Geschlechtsverkehr mit einem männlichen Partner ausschließen und Frauen, deren Partner sterilisiert wurden durch eine Vasektomie oder andere Methode.
 Medizinisch anerkannte Verhütungsmethoden können folgende mit einschließen: hormonelle Kontrazeptiva, Intrauterinpessar und doppelte Verhütung. Akzeptierte präventive Methoden schließen die totale Abstinenz nach dem Ermessen des Untersuchungsleiters mit ein, in Fällen, in denen die Compliance durch das Alter des Teilnehmers, die Arbeit, den Lebensstil oder die sexuelle Orientierung sichergestellt werden kann. Eine periodische Abstinenz (z.B. Kalender, Ovulation, symptothermale Verhütung oder eine Abstinenz bis 4 Tage nach der Ovulation) oder Koitus interruptus sind keine akzeptierten Methoden der Verhütung.
 Eine sichere Methode der Verhütung muss für die gesamte Dauer der Studie angewendet werden.

E.4

Principal exclusion criteria

1. Epilepsy
2. Medication with known CNS effects
3. Severe mental retardation
4. Side effects during previous medication with and contraindications to LTG and/or LOV and/or TMS
5. Psychiatric diseases
6. Previous history of allergic reactions with LTG and LOV medications
7. Potentially unreliable patients
8. Patients who are not suitable for the study in the opinion of the investigator
9. Pregnancy (incl. positive urine pregnancy test)
10. Persons who are incapable of giving consent or do not understand the aim or rationale of the study.

 Epilepsie
 Medikation mit nachgewiesener ZNS Wirksamkeit
 Schwere mentale Retardierung
 Nebeneffekte unter einer vorangegangenen Medikation mit Lamotrigin und / oder Lovastatin und / oder bei der TMS.
 Psychiatrische Erkrankungen
 Vorangegangene allergische Reaktion auf die Studienmedikation
 Potentiell unzuverlässige Patienten
 Patienten, die nach Ansicht des Studienleiters nicht für die Studie geeignet sind.

Es können keine Patienten eingeschlossen die nicht selbständig ihr Einverständnis geben können und die nicht in der Lage den Sinn dieser Studie zu verstehen.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint:
The primary efficacy endpoint analyses will be performed in three separate testing procedures:
I: Lovastatin vs. placebo on group 1
II: Lamotrigine vs. placebo on group 1
III: Lamotrigine vs. placebo on group 2
The global significance level will be 5%. Since experiments I and II are done on the same set of patients, the significance level for those two experiments will each be 2.5%. The significance level of experiment III will be 5%. The primary endpoint analysis will consist of three series of three paired samples two-sided t-tests, comparing MEP under Verum vs. placebo at the three measurement time points. The local significance level will be adjusted using the Bonferroni-Holm procedure.
All analyses will be performed on the full analysis set (FAS-I, FAS-II, FAS-III), consisting of all patients who delivered a full set of MEP measurements after interventional TMS within the corresponding experiment.

Primärer Endpunkt
Die Analyse besteht aus drei separaten Testprozeduren. Das globale Signifikanzniveau (α) liegt bei 5%. Da Experiment I und II auf dem gleichen Kollektiv durchgeführt werden, das α von Exp. I und II beträgt jeweils 2,5%. Das α von Exp. III bleibt bei 5%. Da MEP jeweils an drei Zeitpunkte gemessen wird, besteht die Analyse aus drei zweiseitigen T-Tests für verbundene Stichproben pro Experiment mit Bonferroni-Holm Justierung vom α.

E.5.1.1

Timepoint(s) of evaluation of this end point

Lovastatin and Lamotrigin have 2 timepoints

es gibt bei Lovastatin und Lamotrigin je 2 Zeitpunkte

E.5.2

Secondary end point(s)

Analyses of baseline data, secondary endpoints, and safety data will be done using appropriate descriptive statistics and paired samples tests for difference between the two study groups. All tests will be two-sided with an exploratory significance level of 5%. No adjustment for multiple comparisons will be done.
Another endpoint is the comparison of LTG and LOV effects on synaptic plasticity and attentional performance in the NS group.

Sekundäre Endpunkte
Die Analyse besteht aus geeignete beschreibende Statistiken und Tests für verbundene Stichproben um die Gruppendifferenzen zu verdeutlichen. Alle Tests werden zweiseitig mit α von 5% explorativ gerechnet. Keine Justierung für multiples Testen wird angewendet.
Safety
Inzidenzraten von AEs werden pro Therapiegruppe und Experiment angegeben. Die Analyse basiert auf dem Safety Set, der aus allen Patienten, welche Studienmedikation genommen haben, besteht.

E.5.2.1

Timepoint(s) of evaluation of this end point

Lovastatin and Lamotrigin have 2 timepoints

es gibt bei Lovastatin und Lamotrigin je 2 Zeitpunkte

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

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

Yes

E.6.13.1

Other scope of the trial description

Basic science

Naturwissenschaftliche Basisinformationen

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

Yes

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

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

Last Patient Last Visit is the end of the trial

Die letzte Visite des letzten Patienten ist das Ende der Studie.

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.1.1.1

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)

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)

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

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 study patients regardless of whether the study end
according to the protocol or early / non-terminated according to
protocol, the patient get continued Treatment by Physician or clinic
standard therapie.

Nach Ende der Studie können Patienten unabhängig davon, ob die
Studie protokollgemäß oder vorzeitig/nicht-protokollgemäß beendet
wurde, bekommen die Patienten eine Weiterbehandlung beim Hausarzt
oder die Standard Therapie der jeweiligen Klinik in der der Patient
liegt.

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

2018-02-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-13

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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