Clinical Trials Register

Summary
EudraCT Number:	2011-001711-31
Sponsor's Protocol Code Number:	D1050238
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:	2012-03-29
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

2011-001711-31

A.3

Full title of the trial

A double-blind, placebo-controlled, randomized withdrawal study of lurasidone for the maintenance treatment of subjects with schizophrenia

Studio di sospensione randomizzato, in doppio cieco, controllato con placebo condotto su lurasidone per il trattamento di mantenimento di soggetti affetti da schizofrenia

A.3.1

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

A double-blind, placebo-controlled, randomized withdrawal study of lurasidone for the maintenance treatment of subjects with schizophrenia

Studio di sospensione randomizzato, in doppio cieco, controllato con placebo condotto su lurasidone per il trattamento di mantenimento di soggetti affetti da schizofrenia

A.3.2

Name or abbreviated title of the trial where available

PEARL Mainteinance

A.4.1

Sponsor's protocol code number

D1050238

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01435928

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	PharmaNet/i3
B.5.2	Functional name of contact point	April Buffaloe
B.5.3	Address:
B.5.3.1	Street Address	Constitution Drive
B.5.3.2	Town/ city	Raleigh, NC
B.5.3.3	Post code	27615
B.5.3.4	Country	United States
B.5.4	Telephone number	001 919 7908683
B.5.5	Fax number	001 973 2419870
B.5.6	E-mail	abuffaloe@pharmanet-i3.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.3.4	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	Lurasidone
D.3.9.1	CAS number	367514-87-2
D.3.9.2	Current sponsor code	SM-13496
D.3.9.4	EV Substance Code	SUB32185
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
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

Schizophrenia

Schizofrenia

E.1.1.1

Medical condition in easily understood language

Schizophrenia is a psychotic disorder (or a group of disorders) marked by severely impaired thinking, emotions, and behaviors.

La schizofrenia è un disordine psicotico (o un gruppo di disordini) carattezzati da capacità di pensiero, emozioni e comportamenti gravemente compromessi.

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	10039626
E.1.2	Term	Schizophrenia
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate the efficacy of lurasidone for the maintenance treatment of subjects with schizophrenia.

L’obiettivo primario del presente studio è quello di valutare l’efficacia di lurasidone per il trattamento di mantenimento di soggetti affetti da schizofrenia.

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are to evaluate the safety and tolerability of lurasidone for the maintenance treatment of subjects with schizophrenia.

Gli obiettivi secondari del presente studio sono quelli di valutare la sicurezza e la tollerabilità di lurasidone per il trattamento di mantenimento dei soggetti affetti da schizofrenia.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Screening and Open-label Stabilization Phase 1 Subject is ≥ 18 and ≤ 75 years of age, on the day of signing the informed consent. 2. Subject meets DSM-IV-TR criteria for a primary diagnosis of schizophrenia [including disorganized (295.10), paranoid (295.30), undifferentiated (295.90) subtypes as established by clinical interview (using the DSM-IV-TR as a reference and confirmed using the SCID-CT)]. The duration of the subject`s illness whether treated or untreated must be ≥ 1 year. 3. Subject has had at least one prior episode of psychotic exacerbation as judged by the Investigator in the two years preceding screening. 4. Subject has a PANSS Total score ≥ 80 with a score ≥ 4 on 1 or more of any PANSS Positive subscale items at screening and open-label baseline (Visit 2). 5. Subject has a CGI-S score of ≥ 4 at screening and open-label baseline (Visit 2). Double-blind Phase 1. a PANSS Total score ≤ 70, a CGI-S score < 4 and a PANSS item score of ≤4 (moderate or less)on all PANSS Positive subscale items over at least 12 weeks with the allowance of two excursions (except during the last 4 weeks of the open-label phase) assessed at weekly study visits: • An excursion is defined as a PANSS total score up to a maximum of 80 and/or CGI-S score up to a maximum of 4 and/or a PANSS Positive subscale item score up to a maximum of 5. 2. a PANSS item score of ≤ 4 (moderate or less) on all item G8 (uncooperativeness) 3. taking a stable dose of lurasidone for the last 4 weeks of the openlabel phase.

Screening e Stabilizzazioni in aperto: • il paziente ha ≥ 18 e ≤ 75 anni di età, il giorno della firma del consenso informato. • Soddisfa i criteri DSM-IV-TR per una diagnosi primaria di schizofrenia [inclusi sottotipi disorganizzati (295.10), paranoidi (295.30), indifferenziati (295.90), come stabilito dall’intervista clinica (utilizzando DSM-IV-TR come riferimento e confermato dalla SCID-CT)]. La durata della malattia del soggetto trattata o non trattata deve essere ≥ 1 anno. • Ha manifestato almeno un episodio precedente di riacutizzazione psicotica, come ritenuto dallo sperimentatore nei due anni precedenti lo screening. • Un punteggio PANSS totale ≥ 80 con un punteggio ≥ 4 in 1 o più delle voci della sottoscala positiva PANSS allo screening e alla visita basale dell`open label (Visita 2). • Punteggio CGI-S ≥ 4 allo screening e alla visita basale dell`open label (Visita 2). Fase in doppio cieco: • un punteggio PANSS totale ≤ 70, un punteggio CGI-S < 4 e un punteggio ≤4 (moderato o inferiore) agli items della sub-scala Postiviva PANSS con la concessione di due escursioni eccetto durante le ultime 4 settimane della fase in aperto:  un’escursione è definita come un punteggio PANSS totale fino a un massimo di 80 e/o di CGI-S fino a un massimo di 4 e/o un punteggio sino ad un massimo di 5 nella sottoscala Positiva PANSS. • un punteggio di voci PANSS ≤ 4 (moderato o inferiore) nella voce G8 (non cooperazione) • i soggetti devono inoltre assumere una dose stabile di lurasidone nelle ultime 4 settimane della fase in aperto.

E.4

Principal exclusion criteria

Screening and Open-label Stabilization Phase 1. Subject has a DSM-IV Axis I or Axis II diagnosis other than schizophrenia that has been the primary focus of treatment within 3 months of screening. 2. Subject answers `yes` to `Suicidal Ideation` item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) on the C-SSRS assessment at screening (in the past month)or baseline. 3. Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically significant impaired hepatic function through clinical and laboratory evaluation. 4. Subject with Type 1 or Type 2 insulin-dependent diabetes. 5. Subject has any abnormal laboratory parameter at screening that indicates a clinically significant medical condition as determined by the Investigator. 6. Subject has a prolactin concentration > 100 ng/mL at screening or has a history of pituitary adenoma. 7. Subject is judged to be resistant to antipsychotic treatment defined as any one of the following: a. failure to respond to > 2 marketed antipsychotic agents, given at an adequate dose and for an adequate duration (within the past 2 years) b. history of treatment with clozapine for refractory psychosis Double-blind Phase 1. Subject who in the Investigator`s judgment have been non-compliant with study medication and/or study assessments during the open-label stabilization phase.

Screening e Stabilizzazioni in aperto: • Diagnosi di un disturbo di Asse I o di Asse II, differenti dalla schizofrenia, che rappresentano il fulcro primario del trattamento entro i 3 mesi di screening. • Il soggetto che risponde “sì” alla voce 4 dell’“Ideazione suicidaria” (ideazione suicidaria attiva con una certa intenzione di agire, senza un piano specifico) o alla voce 5 (ideazione suicidaria attiva con una intenzione e un piano specifici) nella valutazione della scala C-SSRS (Columbia-Suicide Severity Rating Scale) allo screening (nel mese precedente) e al basale. • Presenta una concentrazione di prolattina > 100 ng/ml allo screening o un’anamnesi di adenoma pituitario. • Il soggetto viene giudicato resistente al trattamento antipsicotico, definito come uno dei seguenti: o mancata risposta a > 2 farmaci antipsicotici in commercio, somministrati ad una dose adeguata e per una durata appropriata (negli ultimi 2 anni) o anamnesi di trattamento con clozapina per psicosi refrattaria • È improbabile che il soggetto raggiunga una condizione stabile per ≥ 12 settimane durante la fase in aperto con lurasidone, in base a a quanto evidenziato dall’anamnesi psichiatrica e/o dall’attuale presentazione. • Ha ricevuto gli antipsicotici in forma deposito a meno che l’ultima iniezione fosse almeno un ciclo di trattamento o almeno 30 giorni (la più lunga delle due) precedente alla fase di screening. • Il farmaco antipsicotico attuale supera la dose massima raccomandata (specifica per il paese) allo screening o prima dello screening e, a giudizio dello sperimentatore, è improbabile che risponda alle dosi standard di lurasidone. • Necessita il trattamento con un qualsiasi potente inibitore o induttore del citocromo P450 3A4 (CYP3A4) durante lo studio. • Test positivo all’abuso di droghe allo screening. Se un soggetto risulta positivo al test per i cannabinoidi, lo sperimentatore valuterà la capacità del soggetto di astenersi dall’usare tale droga durante lo studio. Doppi Cieco • I soggetti che a giudizio dello sperimentatore non hanno evidenziato adesione alla prescrizione del farmaco in studio durante la fase di stabilizzazione in aperto.

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy Endpoint 1. An increase from double-blind phase baseline in both PANSS Total score of ≥ 25% (see Appendix 7) and a CGI-S worsening of ≥ 1 point, for two consecutive visits, occurring no more than 10 days apart. 2. At any single visit a PANSS item score of ≥ 5 (moderately severe) on hostility or uncooperativeness, or a PANSS item score ≥ 5 on ≥ 2 items of unusual thought content, delusions, conceptual disorganization, or hallucinatory behavior. 3. Initiation of any of the following treatment interventions, for any reason, including worsening schizophrenia, deliberate self injury /aggressive behavior or suicidal ideation: a) the initiation of an antipsychotic agent (other than the study drug lurasidone) b) the initiation or need for an increase in dose of an antidepressant or mood stabilizer c) an increase of lorazepam (or equivalent) dosage ≥ 2 mg/day for a minimum of 3 days relative to the previous dose d) transfer to an increased level or increased intensity of psychiatric care e) initiation of electroconvulsive therapy. 4 Insufficient clinical response (or exacerbation of underlying disease) reported as an adverse event as determined by the Principal Investigator. 5 Deliberate self-injury or repeated aggressive behavior; active suicidal or homicidal ideation or attempt. 6 Psychiatric hospitalization (voluntary or involuntary) due to worsening schizophrenia.

1. An increase from double-blind phase baseline in both PANSS Total score of ≥ 25% (see Appendix 7) and a CGI-S worsening of ≥ 1 point, for two consecutive visits, occurring no more than 10 days apart. 2. At any single visit a PANSS item score of ≥ 5 (moderately severe) on hostility or uncooperativeness, or a PANSS item score ≥ 5 on ≥ 2 items of unusual thought content, delusions, conceptual disorganization, or hallucinatory behavior. 3. Initiation of any of the following treatment interventions, for any reason, including worsening schizophrenia, deliberate self injury /aggressive behavior or suicidal ideation: a) the initiation of an antipsychotic agent (other than the study drug lurasidone) b) the initiation or need for an increase in dose of an antidepressant or mood stabilizer c) an increase of lorazepam (or equivalent) dosage ≥ 2 mg/day for a minimum of 3 days relative to the previous dose d) transfer to an increased level or increased intensity of psychiatric care e) initiation of electroconvulsive therapy. 4 Insufficient clinical response (or exacerbation of underlying disease) reported as an adverse event as determined by the Principal Investigator. 5 Deliberate self-injury or repeated aggressive behavior; active suicidal or homicidal ideation or attempt. 6 Psychiatric hospitalization (voluntary or involuntary) due to worsening schizophrenia.

E.5.1.1

Timepoint(s) of evaluation of this end point

visits 1-26

E.5.2

Secondary end point(s)

The secondary efficacy endpoints are: • Time to all-cause discontinuation • PANSS Total score and PANSS subscores (positive, negative, general psychopathology and excitability) • Clinical Global Impression, Severity of Illness (CGI-S) score • MADRS total score • Short Form-12 Health Survey (SF-12) • Modified SLOF total score and SLOF subscale scores (social functioning and community living skills) • Brief Adherence Rating Scale • Smoking questionnaire • Intent to Attend assessment

• Tempo intercorso fino alla sospensione per una qualsiasi causa • • Time to all-cause discontinuation • PANSS Total score and PANSS subscores (positive, negative, general psychopathology and excitability) • Clinical Global Impression, Severity of Illness (CGI-S) score • MADRS total score • Short Form-12 Health Survey (SF-12) • Modified SLOF total score and SLOF subscale scores (social functioning and community living skills) • Brief Adherence Rating Scale • Smoking questionnaire • Intent to Attend assessment

E.5.2.1

Timepoint(s) of evaluation of this end point

visits 1-26

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

Yes

E.6.11

Pharmacogenomic

Yes

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

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

India

Russian Federation

South Africa

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

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

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)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

1098

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

122

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

414

F.4.2.2

In the whole clinical trial

1220

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)

Subjects will be referred back to their treating psychiatrist for proper aftercare

i pazienti saranno seguiti dai loro psichiatri dopo il trattaemnto

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

2012-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-08-06

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