Clinical Trials Register

Summary
EudraCT Number:	2010-022638-96
Sponsor's Protocol Code Number:	CAFQ056B2214
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-20
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2010-022638-96

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of AFQ056 in adolescent patients with Fragile X Syndrome

Studio randomizzato, in doppio cieco, controllato verso placebo per valutare l'efficacia e la sicurezza di AFQ056 in pazienti adolescenti con Sindrome della X Fragile

A.3.1

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

A study to evaluate the efficacy of AFQ056 in treating abnormal behaviors showed by adolescents (12-17 year-old) with Fragile X Syndrome

Uno studio per valutare l'efficacia di AFQ056 nel trattamento di comportamenti anomali in adolescenti (12-17 anni) con Sindrome dell'X Fragile

A.4.1

Sponsor's protocol code number

CAFQ056B2214

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	NOVARTIS FARMA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NOVARTIS FARMA
B.5.2	Functional name of contact point	Drug Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1
B.5.3.2	Town/ city	ORIGGIO (VA)
B.5.3.3	Post code	21040
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 02 96541
B.5.5	Fax number	+39 02 9659066
B.5.6	E-mail	info.italia@novartis.com

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.2.5	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	AFQ056
D.3.2	Product code	AFQ056
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	AFQ056
D.3.9.2	Current sponsor code	AFQ056
D.3.9.4	EV Substance Code	NA
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	100
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	No
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	AFQ056
D.3.2	Product code	AFQ056
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	AFQ056
D.3.9.2	Current sponsor code	AFQ056
D.3.9.4	EV Substance Code	NA
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	25
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	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

Fragile X Syndrome

Sindrome X fragile

E.1.1.1

Medical condition in easily understood language

mental retardation

ritardo mentale

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10017324
E.1.2	Term	Fragile X syndrome
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

To assess the efficacy of three doses of AFQ056 versus placebo in reducing the ABC-C Total score after 12 weeks of treatment in FXS patients with fully-methylated FMR1 gene.

Valutare verso placebo l’efficacia di tre dosi di AFQ056 nella riduzione del punteggio totale della scala Aberrant Behavior Checklist – Community edition (ABC-C) dopo 12 settimane di trattamento in pazienti con FXS con gene FMR1 (Fragile X Mental Retardation 1) completamente metilato.

E.2.2

Secondary objectives of the trial

The secondary objectives will be applied to both FM and PM strata. • To assess the safety and tolerability of AFQ056 after 12 weeks of treatment. • To assess the efficacy of three doses of AFQ056 versus placebo on the global improvement of symptoms in Fragile X patients using the Clinical Global Impression - Improvement (CGI-I) scale after 12 weeks of treatment. • To assess the efficacy of AFQ056 versus placebo in reducing irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity, and inappropriate speech assessed by the corresponding individual subscales of the ABC-C after 12 weeks of treatment. • To assess the efficacy of AFQ056 versus placebo with respect to the proportion of patients with clinical response, where response is defined as reduction of at least 25% from baseline in the ABC-C total score and a score of 1 (very much improved) or 2 (much improved) on the CGI-I scale at Week 12. • PLS SEE PROTOCOL

Valutare verso placebo l’efficacia di tre dosi di AFQ056 nel ridurre il punteggio totale della scala ABCC dopo 12 settimane di trattamento in pazienti con FXS con gene FMR1 parzialmente metilato. Per maggiori dettagli consultare il capitolo 2 del protocollo originale.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria at Screening (V1), unless another time point prior to randomization is specified: 1. the caregiver/legal guardian must be able to communicate well with the investigator and must understand and support the study requirements by providing written informed consent. Where possible the patient should also provide his or her written assent (in accordance with local ethical/regulatory requirements); 2. male or female, between 12 and 17 years of age, inclusive; 3. have a previous diagnosis of FXS based upon documented genetic testing results (full mutation >200 CGG repeats). The diagnosis will need to be confirmed by genetic testing prior to the patient entering the Placebo Run-in Period; 4. have a Clinical Global Impression Severity Score (CGI-S) of ≥ 4 (moderately ill); 5. have a score of > 20 in the ABC-C total scale; 6. have an IQ < 70 as measured by the Leiter International Performance Scale – Revised (Leiter-R); 7. have a caregiver who spends, on average, at least six hours per day with the patient, who is willing and capable of supervising treatment, providing input into efficacy and safety assessments, and accompanying the patient to all study visits; 8. have a caregiver who, in the opinion of the investigator, is a reliable source of information regarding the patient and the severity of his/her disease.

Criteri di inclusione • Eta' compresa tra i 12 e i 17 anni, estremi inclusi • Pazienti di sesso maschile e femminile • Diagnosi precedente di FXS basata su risultati documentati di test genetici (mutazione completa > 200 ripetizioni CGG). La diagnosi dovra' essere confermata con test genetico prima dell’ingresso del paziente nel periodo di run-in con placebo • Punteggio Clinical Global Impression Severity Score (CGI-S) ≥ 4 (malattia moderata) • Punteggio totale > 20 alla scala ABC-C • QI < 70 misurato tramite la scala Leiter International Performance Scale-Revised (Leiter-R) • Pazienti con una persona che si prende cura di loro (caregiver) che trascorre in media almeno sei ore al giorno con il paziente, disponibile e in grado di supervisionare il trattamento, di fornire informazioni per le valutazioni di efficacia e di sicurezza e di accompagnare il paziente a tutte le visite dello studio • Pazienti con un caregiver che, a giudizio dello sperimentatore, costituisce una fonte di informazioni affidabile sul paziente e la severita' della sua patologia.

E.4

Principal exclusion criteria

Patients fulfilling any of the following criteria prior to randomization (V3) are not eligible for inclusion in this study: 1. female patients who are sexually active at any time during the study Sexual activity should be carefully evaluated by the Investigator and if sexual activity is confirmed or suspected, the female participant should not be enrolled into the study. Furthermore, the Investigator should continue to evaluate the possibility of sexual activity throughout the study and the caregiver/legal guardian should be instructed to immediately inform the Investigator if the female participant becomes or is suspected to have become sexually active during the study. In these cases, appropriate actions should be taken by the Investigator and the patient must be discontinued from the study; 2. any advanced, severe or unstable disease that may interfere with the primary or secondary study outcome evaluations or put the patient at special risk; 3. past medical history of clinically significant ECG abnormalities or QTcF > 450 msec for males and > 470 msec for females at screening or baseline; 4. lab screening values that include AST, ALT, GGT, total bilirubin or creatinine ≥ 1.5 X ULN (upper limit of normal) for the central laboratory; total or unconjugated (indirect) bilirubin levels up to 3 X ULN for the central laboratory are allowed if the patient has a diagnosis of Gilbert’s syndrome; 5. have history of major surgery or major medical event that require hospitalization or major surgery within the past 6 months, unless they recovered fully or are considered clinically stable; 6. donated or lost more than 2.4 mL of blood per kg of body weight within (4) weeks prior to Screening (V1) or longer if required by local regulation; 7. history and/or presence of schizophrenia, bipolar disease, psychosis, confusional states and/or repeated hallucinations as per Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria; 8. history of suicidal behavior or considered a high suicidal risk; 9. history of severe self-injurious behavior; 10. history of uncontrolled seizure disorder or resistant to therapy within the past 2 years (Patients who are clinically stable under anti-convulsant therapy for the past 2 years are allowed); 11. history of clinically significant allergies requiring hospitalization or non-inhaled corticosteroid therapy (asthma, anaphylaxis, etc.); 12. history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether or not there is evidence of local recurrence or metastases; 13. pregnant or nursing (lactating) females, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG serum pregnancy test; 14. patients on any treatment regimen, including psychotropic and/or current anticonvulsant therapy that has not been stable for ≥ 6 weeks prior to randomization; PLS SEE PROTOCOL

Criteri di esclusione • Pazienti di sesso femminile sessualmente attive in qualsiasi momento durante lo studio • Anamnesi e/o presenza di schizofrenia, malattia bipolare, psicosi, stati confusionali e/o allucinazioni ripetute secondo i criteri del DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) • Anamnesi di comportamento suicida o pazienti considerati ad alto rischio di suicidio • Anamnesi di grave comportamento autolesionistico • Anamnesi di disordine epilettico non controllato o resistente alla terapia nei 2 anni precedenti (i pazienti clinicamente stabili in trattamento con terapia anti-convulsiva nei 2 anni precedenti sono considerati eleggibili) • Anamnesi di allergie clinicamente significative che abbiano richiesto ricovero ospedaliero o terapia cortisonica non per inalazione (asma, anafilassi, ecc.) • Qualsiasi regime di trattamento, compreso il trattamento psicotropo e/o l’attuale terapia anticonvulsivante non stabile per ≥ 6 settimane prima della randomizzazione • Trattamento attuale con piu' di due farmaci psicoattivi, esclusi gli anti-epilettici • Pazienti che fanno uso (o che hanno fatto uso nelle 6 settimane precedenti la randomizzazione) di farmaci concomitanti che sono potenti inibitori o induttori di CYP3A4 • Pazienti che hanno utilizzato agenti glutamatergici (riluzolo, memantina, ecc.) o litio nelle 6 settimane precedenti la randomizzazione • Pazienti che hanno pianificato di iniziare o di apportare variazioni a interventi farmacologici o non farmacologici nel corso dello studio • Pazienti non in grado di deglutire il farmaco in studio, come dimostrato dal test di deglutizione con capsule di placebo alla visita di screening • Pazienti con un peso corporeo inferiore ai 32 kg (= 10° percentile del peso corporeo per un adolescente di 12 anni). Per maggiori dettagli consultare i paragrafi 5.1 e 5.2 del protocollo originale.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy analyses will be based on the Aberrant Behavour Checklist - Community Edition (ABC-C) Total score.

Valutazioni di efficacia • ABC-C (Aberrant Behavior Checklist – Community edition)

E.5.1.1

Timepoint(s) of evaluation of this end point

At multiple visits: -7, -4, -2 weeks before Baseline Visit at baseline 2, 4, 8, 12 weeks after baseline

Più visite: -7, -4, -2 settimane prima del Baseline Visita ''baseline'' 2, 4, 8, 12 settimane dopo il ''baseline''

E.5.2

Secondary end point(s)

- Aberrant Behavour Checklist - Community Edition (ABC-C): Total score and subscales - Clinical Global Impression - Improvement (CGI) - Repetitive Behavior Scale - Revised (RBS-R)

- Aberrant Behavour Checklist - Community Edition (ABC-C): Punteggio totale e le sottoscale - Clinical Global Impression - Miglioramento (CGI) - Repetitive Behavior Scale - Revised (RBS-R)

E.5.2.1

Timepoint(s) of evaluation of this end point

ABC-C: -7, -4, -2 weeks before Baseline; Visit at baseline; 2, 4, 8, 12 weeks after baseline CGI: Visits at 2, 4, 8 12 weeks after Baseline RBS-R: Visit at -3 weeks before Baseline; Visit at Baseline; Visits at 4 and 12 weeks after Baseline

ABC-C: -7, -4, -2 settimane prima Baseline; Visita al baseline; 2, 4, 8, 12 settimane dopo baseline CGI: Visits at 2, 4, 8 12 settimane dopo Baseline RBS-R: Visit at -3 settimane prima del Baseline; Visita al Baseline; Visite 4 e 12 settimane dopo Baseline

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability

tollerabilità

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

Yes

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

Yes

E.8.2.3.1

Comparator description

- Stesso farmaco ad altro dosaggio

- same IMP used at different dosage

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Switzerland

United States

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

end of study (LVLS) : 8/April/2013

data di fine studio (LPLV): 8/Aprile/ 2013

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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:

180

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:

180

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 2012-03-20.

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

180

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)

Expected normal treatment

Previsto trattamento normale

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

2011-07-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-04-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-01-06

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