Clinical Trials Register

Summary
EudraCT Number:	2013-004903-37
Sponsor's Protocol Code Number:	D1050326
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Not Authorised
Date on which this record was first entered in the EudraCT database:	2014-04-04
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

2013-004903-37

A.3

Full title of the trial

A RANDOMIZED, 6-WEEK, DOUBLE-BLIND, PLACEBO-CONTROLLED, FLEXIBLE DOSE, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LURASIDONE IN CHILDREN AND ADOLESCENT SUBJECTS WITH BIPOLAR I DEPRESSION

Studio randomizzato della durata di 6 settimane, a gruppi paralleli, in doppio cieco, controllato con placebo, a dose flessibile per valutare l’efficacia e la sicurezza di lurasidone in soggetti pediatrici e adolescenti affetti da depressione bipolare di tipo I

A.3.1

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

The purpose of this research study is to evaluate the safety and effectiveness of lurasidone (20 mg/day to 80 mg/day) compared to a placebo for use in children and adolescent subjects with bipolar I depression.

Scopo di questo studio di ricerca è la valuazione della sicurezza e l’efficacia di lurasidone (da 20mg/die a 80 mg/die) rispetto a placebo in bambini e adolescenti con depressione bipolare di tipo I.

A.4.1

Sponsor's protocol code number

D1050326

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00844857

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	SUNOVION PHARMACEUTICALS INC.
B.1.3.4	Country	United States
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	Sunovion Pharmaceuticals Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sunovion Pharmaceuticals Inc.
B.5.2	Functional name of contact point	Robert Goldman
B.5.3	Address:
B.5.3.1	Street Address	One Bridge Plaza Suite 510
B.5.3.2	Town/ city	Fort Lee,
B.5.3.3	Post code	NJ 07024
B.5.3.4	Country	United States
B.5.4	Telephone number	(1) 201-592-2050
B.5.6	E-mail	Robert.Goldman@sunovion.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	Yes
D.2.1.1.1	Trade name	LATUDA
D.2.1.1.2	Name of the Marketing Authorisation holder	Sunovion Pharmaceuticals Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	LURASIDONE
D.3.2	Product code	SM-13496
D.3.4	Pharmaceutical form	Film-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	Lurasidone Hydrochloride
D.3.9.1	CAS number	367514-88-3
D.3.9.2	Current sponsor code	SM-13496
D.3.9.3	Other descriptive name	Lurasidone Hydrochloride
D.3.9.4	EV Substance Code	SUB34204
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 40
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	Film-coated 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

Bipolar I depression

Depressione bipolare

E.1.1.1

Medical condition in easily understood language

Bipolar I depression

Depressione bipolare di tipo I

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10004936
E.1.2	Term	Bipolar depression
E.1.2	System Organ Class	100000004873

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 the efficacy of lurasidone (20 - 80 mg/day flexibly dosed) compared with placebo in children and adolescent subjects with bipolar I disorder, most recent episode depressed, with or without rapid cycling disease course, and without psychotic features (diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 5th Ed. [DSM-V] criteria) as measured by the change from Baseline in the Children's Depression Rating Scale, Revised (CDRS-R) total score.

valutare l’efficacia di lurasidone (20-80 mg/die somministrato in modo flessibile) rispetto al placebo in soggetti pediatrici e adolescenti con disturbo bipolare di tipo I, episodio di depressione più recente, con o senza decorso della malattia a cicli rapidi e senza caratteristiche psicotiche (diagnosticate secondo i criteri della V Edizione del Manuale diagnostico e statistico dei disturbi mentali (Diagnostic and Statistical Manual of Mental Disorders, 5th ed. [DSM-V]), come misurato mediante la variazione dal basale del punteggio totale rettificato della scala di valutazione della depressione in età pediatrica (Children’s Depression Rating Scale, revised [CDRS-R]).

E.2.2

Secondary objectives of the trial

Global severity as assessed by the Clinical Global Impression-Bipolar Version, Severity of Illness (CGI-BP-S) score (depression).
Other secondary objectives of this study include evaluation of the following:
 Change in anxiety symptoms;
 Change in quality of life;
 Change in social and psychiatric functioning
 Treatment response;
 Symptom remission;
 Change in attention-deficit/hyperactivity symptoms;
 Safety and tolerability of lurasidone 20 - 80 mg/day flexibly dosed;
 Treatment-emergent mania.

Gravità globale, come valutata mediante il punteggio (depressione) della scala di gravità sull’impressione clinica globale, versione inerente al disturbo bipolare (Clinical Global Impression-Bipolar Version, Severity of Illness, CGI-BP-S).
Altri obiettivi secondari dello studio includono la valutazione dei seguenti elementi:
– variazione nei sintomi di ansia
– variazione nella qualità di vita
– variazione nella funzione sociale e psichiatrica
– risposta al trattamento
– remissione sintomatologica
– variazione dei sintomi di attenzione/iperattività
– sicurezza e tollerabilità di 20-80 mg/die di lurasidone in dosaggio flessibile
– episodi maniacali emergenti dal trattamento

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male or female subjects 10 to 17 years of age, inclusive with bipolar I disorder, most recent episode depressed with or without rapid cycling disease course (≥ 4 episodes of mood disturbance but < 8 episodes in the previous 12 months) and without psychotic features (diagnosed by DSM-V criteria, and confirmation of the bipolar I disorder diagnosis by an adequately trained clinician at the time of screening, by means of the Schedule for Affective Disorders and Schizophrenia for School-age Children [K-SADS-PL]). Children's Depression Rating Scale, Revised (CDRS-R) total score ≥ 45 at screening and Baseline. Young Mania Rating Scale (YMRS) score ≤ 15 (with YMRS Item 1 [elevated mood] score ≤ 2) at screening and Baseline.

soggetti di sesso maschile o femminile di età compresa tra 10 e 17 anni, comprendenti soggetti con disturbo bipolare di tipo I, episodio di depressione più recente, con o senza decorso della malattia a cicli rapidi (≥ 4 episodi di alterazione dell’umore, ma < 8 episodi negli ultimi 12 mesi) e senza caratteristiche psicotiche (diagnosticate secondo i criteri del DSM-V e con diagnosi confermata di disturbo bipolare tipo I, da parte di un medico adeguatamente formato, al momento dello screening, mediante la pianificazione dei disturbi affettivi e della schizofrenia per bambini in età scolare [K-SADS-PL]). Punteggio totale rettificato della scala di valutazione della depressione in età pediatrica (CDRS-R) ≥ 45 allo screening e al basale. Punteggio della scala di valutazione degli episodi maniacali nei minori (YMRS) ≤ 15 (con punteggio dell’item 1 [umore elevato] della YMRS ≤ 2) allo screening e al basale.

E.4

Principal exclusion criteria

Has an Axis I or Axis II diagnosis other than bipolar I disorder and/or concomitant ADHD that has been the primary focus of treatment within 3 months of screening. Has a history or current diagnosis of intellectual disability, Autism Spectrum Disorder, neuroleptic malignant syndrome, or any neurologic disorder, severe head trauma, or any unstable medical condition. CDRS-R total score > 85 at screening or Baseline.

diagnosi di asse I o asse II diversa dal disturbo bipolare di tipo I, che sia stata l’obiettivo primario del trattamento nei 3 mesi dello screening. Anamnesi o diagnosi attuale di disabilità intellettiva, disturbo dello spettro autistico, sindrome neurolettica maligna o qualsiasi disturbo neurologico, grave trauma cranico o qualsiasi condizione medica instabile. Punteggio totale della CDRS-R ≥ 85 allo screening o al basale.

E.5 End points

E.5.1

Primary end point(s)

Change in the Children Depression Rating Scale, Revised (CDRS-R) total score as compared to placebo from Double-Blind Baseline to Week 6 (Day 43).

punteggio totale rettificato della scala di valutazione della depressione in età pediatrica (CDRS-R) rispetto al placebo, in doppio cieco dal basale alla Settimana 6

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline through week 6

dal basale alla settimana 6

E.5.2

Secondary end point(s)

Change in Clinical Global Impression-Bipolar Version, Severity of Illness (CGI-BP-S) score (depression) as compared to placebo from Double-Blind Baseline to Week 6 (Day 43).
Other Secondary Efficacy Endpoints:
 Change from Baseline in Pediatric Anxiety Rating Scale (PARS) score as compared to placebo.
 Change from Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) score as compared to placebo.
 Change from Baseline in Clinician-rated Children’s Global Assessment Scale (CGAS) score as compared to placebo.
 Proportion of responders, where response is defined as ≥ 50% reduction from Baseline in adjusted CDRS-R total score at last observation carried forward (LOCF) Endpoint as compared to placebo.
 Proportion of subjects achieving remission, where remission is defined as post-baseline CDRS-R Total Score ≤ 28 and Young Mania Rating Scale (YMRS) total score ≤ 8 and Clinical Global Impressions-Bipolar Version Severity (CGI-BP-S) depression score ≤ 3.
 Change from Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) score as compared to placebo.

variazione del punteggio dello stato di depressione mediante scala di gravità sull’impressione clinica globale, versione inerente al disturbo bipolare (CGI-BP-S) (depressione) rispetto al placebo in doppio cieco dal basale alla Settimana 6 (Giorno 43).
Altri endpoint secondari di efficacia:
– variazione del punteggio della scala di valutazione dell’ansia in età pediatrica (PARS) dal basale rispetto al placebo.
– variazione del punteggio del questionario relativo alla soddisfazione e all’apprezzamento della qualità della vita (PQ-LES-Q) dal basale rispetto al placebo;
– variazione del punteggio della scala di valutazione globale dei bambini valutata dal medico (CGAS) dal basale rispetto al placebo;
– percentuale di responder, dove la risposta è definita come riduzione ≥ 50% rispetto al basale nel punteggio totale rettificato della scala di valutazione della depressione in età pediatrica (CDRS-R) alla conclusione dell’ultima osservazione riportata (Last Observation Carried Forward, LOCF) dell’endpoint rispetto al placebo.
– percentuale di soggetti che hanno raggiunto la remissione, definita come punteggio totale della CDRS-R successivo al basale ≤ 28, punteggio totale della scala di valutazione degli episodi maniacali nei minori (YMRS) ≤ 8 e punteggio dello stato di depressione mediante scala di gravità sull’impressione clinica globale, versione inerente al disturbo bipolare (CGI-BP-S) ≤ 3.
– variazione del punteggio della scala di valutazione dei sintomi del deficit di attenzione/iperattività (ADHD-RS) dal basale rispetto al placebo.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline through week 6

dal basale alla settimana 6

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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

Bulgaria

China

Italy

Romania

Colombia

Korea, Republic of

Malaysia

Puerto Rico

Spain

Mexico

Philippines

Serbia

Ukraine

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

LVLS (last visit last subject)

LVLS (ultima visita dell'ultimo paziente)

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

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:

340

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:

272

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

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

340

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)

11.4.9. Follow-Up: Visit 9 Week 7 (Day 50 ± 2 days: Out-patient)
Subjects who do not continue into the extension study (D1050302) will return to the study site for safety assessments approximately 1 week (7 ± 2 days) after taking their last dose of study drug.

Last paragraph of the section 12.2 (of the protocol): 'Follow-up Procedures Upon Discontinuation or Withdrawal' (pages 53-54)

si faccia riferimento alla sezione del protocollo 11.4.9 “Follow-up: visit 9 week 7” : i soggetti che non partecipano allo studio di estensione (D1050302) ritorneranno al centro dello studio per le valutazioni di sicurezza circa 1 settimana dopo l’assunzione dell’ultima dose di farmaco.
Si faccia inoltre riferimento all’ultimo paragrafo della sezione 12.2 'Follow-up Procedures Upon Discontinuation or Withdrawal' (pag 53-54)

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

2014-05-22

Ethics Committee Opinion of the trial application

Not-Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Evaluation of the anticipated benefits and risks

Measures to minimise pain, discomfort and fear

Inclusion of persons incapable of giving informed consent or other vulnerable populations

Compliance with GCP

Date of Ethics Committee Opinion

2014-07-30

P. End of Trial
P.	End of Trial Status	Not Authorised

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