Clinical Trials Register

Summary
EudraCT Number:	2017-000687-16
Sponsor's Protocol Code Number:	ARIDDS2
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-08
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-000687-16

A.3

Full title of the trial

Novel avenues for the rescue of intellectual disability in Down syndrome

NUOVE STRATEGIE PER IL RECUPERO DELLA DISABILIT¿ INTELLETTIVA NELLA SINDROME DI DOWN

A.3.1

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

Novel avenues for the rescue of intellectual disability in Down syndrome

strategia farmacologiche per migliorare la disabilit¿ intellettiva nella sindrome di Down

A.3.2

Name or abbreviated title of the trial where available

Novel avenues for the rescue of intellectual disability in Down

NUOVE STRATEGIE PER IL RECUPERO DELLA DISABILIT¿

A.4.1

Sponsor's protocol code number

ARIDDS2

A.5.4

Other Identifiers

Name:

ARIDDS 2

Number:

ARIDDS 2

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	AOU FEDERICO II
B.1.3.4	Country	Italy
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	Universit¿ Alma Studiorum Bologna
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dipartimento di Scienze Mediche Traslazionali- sez. di Pediatria
B.5.2	Functional name of contact point	Dipartimento di Pediatria
B.5.3	Address:
B.5.3.1	Street Address	Via Sergio Pansini
B.5.3.2	Town/ city	Napoli
B.5.3.3	Post code	80131
B.5.3.4	Country	Italy
B.5.4	Telephone number	0817463399
B.5.5	Fax number	0817463116
B.5.6	E-mail	iris.scala@unina.it

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	PROZAC - 20 MG/5 ML SOLUZIONE ORALE 1 FLACONE IN VETRO DA 60 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ELI LILLY ITALIA S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	prozac
D.3.2	Product code	25970029
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Yes
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	FLUOXETINA CLORIDRATO
D.3.9.1	CAS number	54910-89-3
D.3.9.2	Current sponsor code	151001_OSSC0070
D.3.9.3	Other descriptive name	fluoxetine
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	10
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

DOWN SYNDROME

SINDROME DI DOWN

E.1.1.1

Medical condition in easily understood language

chromosome 21 trisomy

trisomia del cromosoma 21

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10042801
E.1.2	Term	Syndrome Down's
E.1.2	System Organ Class	100000004850

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 evaluate safety and tolerability of fluoxetine in a pediatric population with Down syndrome

Valutare la sicurezza e la tollerabilit¿ della fluoxetina in una popolazione pediatrica di soggetti con sindrome di Down.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of fluoxetine in ameliorating cognitive performances in children with Down syndrome by measuring improvements of at least one of the hippocampus-connected functions namely: memory, attention and learning skills, visuo-spatial processing function.

Verificare se la fluoxetina sia efficace nel migliorare le performance cognitive di bambini con sindrome di Down, con la dimostrazione di un miglioramento di almeno una delle funzioni connesse all¿ippocampo, come: memoria, attenzione e abilit¿ di apprendimento, capacit¿ di elaborazione visuospaziale.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Subjects of either gender with Down syndrome aged between 5 and 10, extremes included;
- Subjects who gave their consent to participate to the study by informed consent signature from parents or legal tutors before any data collection;
- Subjects in euthyroidism (reference value: FT4) with or without drug therapy;
- Subjects, celiac or not, with negative values at screening for celiac disease (reference value: Antitransglutaminase antibodies IgA);
- Subjects who never took fluoxetine previously.
- Patients not treated with contraindicated concomitant therapies

- Soggetti di entrambi i sessi con sindrome di Down, di età compresa tra i 5 e i 10 anni, estremi inclusi;
- Soggetti che hanno dato il consenso alla partecipazione mediante la firma del modulo di consenso informato da parte dei genitori o dei tutori legali prima dell’inizio della raccolta dati;
- Soggetti in eutiroidismo (valore di riferimento: FT4) con o senza trattamento farmacologico;
- Soggetti, celiaci o non celiaci, con test di screening per malattia celiaca negativo all’arruolamento (valore di riferimento: Ab antitransglutaminasi IgA);
- Soggetti che non hanno mai assunto fluoxetina in
precedenza
- Pazienti non in terapia con trattamenti concomitanti
controindicati

E.4

Principal exclusion criteria

- Subjects aged less than 5 or more than 10;
- Subjects with concomitant neurological diseases other than those expected for the Down syndrome phenotype;
- Subjects with neuropsychiatric diseases: Depressive and Bipolar Disorders;
- Subjects with major malformations requiring prolonged hospitalization;
- Subjects with concomitant medical conditions such as: epilepsy, thyroid dysfunction (not in euthyroidism), diabetes, gastrointestinal,
hepatic or renal problems that may alter the absorption and the metabolism of the experimental drug; patients with bleeding disorders or history of bleeding disorders;
- Subjects with long QT syndrome and/or familiarity of long QT syndrome;
- Subjects with congenital cardiopathy, nocturnal apnea syndrome, pericarditis and myocarditis, hypertension or hypertensive crisis,
blood electrolytes alterations (in particular, potassium and calcium);
- Subjects treated with controindicated concomitant therapies:
Reversibile and irreversibile monoamine oxidase inhibitor: MAOI-A and MAOI-B (selegiline);
Oral anticoagulants, drugs known to affect platelet function (e.g. atypical antipsychotics such as clozapine, phenothiazines, tricyclic antidepressants, aspirin, nonsteroidal anti-inflammatory drugs NSAID’s) or other drugs that may increase risk of bleeding;
Electroconvulsive Therapy (ECT);
St John’s Wort (Hypericumperforatum);
Serotonergic (such as L-tryptophan, tramadol, triptans) and/or neuroleptic drugs;
Phenytoin;
Lithium and tryptophan;
Drugs metabolised by the CYP2D6 isoenzyme: because fluoxetine’s metabolism (like tricyclic antidepressants and other selective serotonin antidepressants) involves the hepatic cytochrome CYP2D6 isoenzyme system, concomitant therapy with drugs also metabolised by this enzyme system may lead to drug interactions. Concomitant
therapy with drugs predominantly metabolised by this isoenzyme, and which have a narrow therapeutic index (such as risperidone, atomoxetine, metaprolol, tamoxifene, flecainide, encainide,
carbamazepine and tricyclic antidepressants), will be not allowed. This will also apply until 5 weeks from fluoxetine withdrawal.
Alcohol
Drug determining a prolonged QT-interval such as class IA and III antiarrhythmic agents, antipsychotic drugs (phenothiazine derivatives, pimozide, aloperidole, tricyclic antidepressant, antibacterial agents (sparfloxacine, moxifloxacine, eritromicine IV, pentamidine, antimalaric drugs (alofantrina) and antihistamine agents (astemizole, mizolastine).
Benzodiazapines. Plasma concentrations of diazepam and alprazolam can increase when fluoxetine is administered in combination.
Antipsychotics. Possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant Fluoxetine.
Anticonvulsants. Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation
of concomitant Fluoxetine treatment.
Drugs Tightly Bound to Plasma Proteins. Because Fluoxetine is tightly bound to plasma proteins, the administration of Fluoxetine to a patient taking another drug that is tightly bound to protein (digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
- Subjects taking one or more of the following: B12 vitamins, folates, minerals (selenium, zinc, and magnesium), gingko biloba, curcumina, amino acids (tryptophan, tyrosine), antioxidant compounds (Q10 coenzyme, green tea extract), fish oil, omega-3
fatty acids, rodiola
- Lack of consent to study participation from parents or legal tutors.

- Soggetti di età inferiore ai 5 anni e superiore a 10 anni;
- Soggetti con problemi neurologici concomitanti diversi da quelli previsti per la sindrome di Down
- Soggetti con disturbi neuropsichiatrici: disordini depressivi e bipolari
- Soggetti con malformazioni maggiori richiedenti
ospedalizzazione prolungata
- Soggetti con patologie concomitanti come: epilessia, disfunzione tiroidea (non in eutiroidismo), diabete, problemi gastrointestinali, epatici o renali che possano alterare l’assorbimento ed il metabolismo del farmaco sperimentale; pazienti con disordini emostatici o con storia di disordini emostatici;
- Soggetti con sindrome del QT lungo e/o con familiarità per sindrome del QT lungo;
- Soggetti con cardiopatia congenita, sindrome da
apnee notturne, pericarditi e miocarditi, ipertensione o crisi ipertensive, alterazioni degli elettroliti sierici (in
particolare potassio e calcio);
- Pazienti in trattamento con terapie concomitanti
controindicate:
inibitori reversibili e irreversibili delle monoaminoossidasi:
MAOI-A e MAOI-B (selegilina);
anticoagulanti orali, farmaci con effetto noto sulla
funzione piastrinica (e.g. antipsicotici atipici come
clozapina, fenotiazine, antidepressivi triciclici, aspirina, antiinfiammatori non steroidei) o altri farmaci che possano aumentare il rischio di sanguinamento;
terapia elettroconvulsiva (ECT);
Erba di ST. John (Hypericum perforatum);
Farmaci serotoninergici (come L-triptofano, tramadolo, triptani) e/o neurolettici;
fenitoina;
litio e triptofano;
farmaci metabolizzati attraverso l’isoenzima CYP2D6: poiché il metabolismo della fluoxetina coinvolge ilcitocromo CYP2D6, terapie concomitanti con farmaci metabolizzati dallo stesso sistema enzimatico potrebbero causare interazioni farmacologiche. Terapie concomitanti con farmaci prevalentemente metabolizzati da questo isoenzima e con uno stretto indice terapeutico (risperidone, atomoxetina, metaprololo, tamoxifene, flecainide, encainide, carbamazepina e antidepressivi triciclici) non saranno consentite. Questo sarà applicato anche nelle 5 settimane successive alla sospensione della fluoxetina;
Alchool;
farmaci determinanti un prolungamento dell’intervallo
QT, quali gli antiaritmici di classe IA e III, farmaci
antipsicotici, agenti antibatterici (sparfloxacina,
moxifloxacina, eritromicina IV, pentamidina, farmaci
antimalarici (alofantrina) e agenti antistaminici
(astemizolo, mizolastina);
benzodiazepine. Le concentrazioni plasmatiche di
diazepam e alprazolam possono aumentare durante
l’assunzione di fluoxetina;
antipsicotici;
anticonvulsivanti (e.g. fenitoina, carbamazepina);
farmaci con elevato legame alle proteine plasmatiche
(e.g. digitossina);
- Soggetti che assumono uno o più dei seguenti: vitamina B12, folati, sali minerali (selenio, zinco e magnesio), ginkgo biloba, curcumina, amminoacidi (triptofano e tirosina), composti antiossidanti (coenzima Q10, estratti del thè verde); olio di pesce, omega 3, rodiola)
- Soggetto che non ha dato il consenso alla
partecipazione mediante la firma del modulo di
consenso informato da parte dei genitori o tutore legale.

E.5 End points

E.5.1

Primary end point(s)

To evaluate safety and tolerability of fluoxetine in a pediatric population with Down syndrome

Tipologia e frequenza degli eventi avversi registrati durante lo studio, inclusi i valori anomali agli esami di laboratorio, considerati clinicamente significativi dallo sperimentatore.

E.5.1.1

Timepoint(s) of evaluation of this end point

Screening, T0, T+1 month, T+3 month, T+6 month, T++6 month, T+12 month

Screening, T0, T+1 mese, T+3 mesi, T+6 mesi, T++6 mesi, T+12 mesi

E.5.2

Secondary end point(s)

Identificare la proporzione di soggetti che ottengono
miglioramenti in almeno una delle funzioni ippocampo ¿ correlate, come: memoria, attenzione e abilit¿ di apprendimento, capacit¿ di elaborazione visuospaziale.

E.5.2.1

Timepoint(s) of evaluation of this end point

T0, T+6 month, T+12 month

T0, T+6 mesi, T+12 mesi

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

study of safety and tollerability of Prozac in pediatric patients with Down syndrome.

studio di sicurezza e tollerabilit¿ del Prozac nella popolazione pediatrica con sindrome di Down

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

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

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.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Information not present in EudraCT

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

LVLS

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.1.1.1

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)

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

pediatric subjects with intellectual disability

soggetti in et¿ pediatrica con disabilit¿ intellettiva

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

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)

Clinic/ neuropsychiatric FU according to Down Syndrome clinical guidelines

Follow up clinico/ neuropsichiatrico infantile secondo le linee guida di Fu della sindrome di Down

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

2017-12-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-24

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

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