Clinical Trials Register

Summary
EudraCT Number:	2009-014469-19
Sponsor's Protocol Code Number:	RECOVERY[OCTUMI-4]
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-08-02
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

2009-014469-19

A.3

Full title of the trial

RECOVERY [OCTUMI-4] Evaluation of Mirtazapine and Folic Acid for Schizophrenia: A Large Simple 2x2 Factorial Trial

RECOVERY [OCTUMI-4] Valutazione di mirtazapina e acido folico nella schizofrenia: uno studio randomizzato, di tipo pragmatico, con disegno fattoriale (2x2)

A.3.1

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

Multicentre randomised double-blind, placebo-controlled 2x2 factorial trial investigating the effects of adding mirtazapine and folic acid to existing therapy for people with schizophrenia.

Trial clinico randomizzato in doppio cieco, multicentrico, con disegno fattoriale (2x2) per valutare l'efficacia dell'aggiunta di mirtazapina e acido folico alla terapia gia' in atto, in pazienti con schizofrenia

A.3.2

Name or abbreviated title of the trial where available

RECOVERY [OCTUMI-4]

A.4.1

Sponsor's protocol code number

RECOVERY[OCTUMI-4]

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN32434568

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	UNIVERSITY OF OXFORD
B.1.3.4	Country	United Kingdom
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	University of Oxford
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Stanley Medical Research Institute
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	UNIVERSITY OF OXFORD
B.5.2	Functional name of contact point	OCTUMI-4 INFORMATION OFFICE
B.5.3	Address:
B.5.3.1	Street Address	WARNEFORD HOSPITAL
B.5.3.2	Town/ city	OXFORD
B.5.3.3	Post code	OX3 7JX
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 1865 226465
B.5.5	Fax number	+0044 1865 223900
B.5.6	E-mail	andrea.cipriani@psych.ox.ac.uk

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	Mirtazapine
D.2.1.1.2	Name of the Marketing Authorisation holder	ALIUD® PHARMA GmbH
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.3.4	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	MIRTAZAPINE
D.3.9.1	CAS number	61337-67-5
D.3.9.4	EV Substance Code	SUB08996MIG
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	30
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	Yes
D.2.1.1.1	Trade name	Folic acid
D.2.1.1.2	Name of the Marketing Authorisation holder	Bilcare GSC (Europe)
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	FOLIC ACID
D.3.9.1	CAS number	59-30-3
D.3.9.4	EV Substance Code	SUB07774MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	400 to 500
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
D.8 Placebo: 2
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

Schizofrenia

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

Is mirtazapine as add-on therapy to antipsychotic treatment more effective than placebo for treatment of positive and negative symptoms of schizophrenia?

La terapia con mirtazapina in aggiunta alla terapia antipsicotica già in atto è più efficace del placebo nel ridurre i sintomi positivi e negativi in pazienti con schizofrenia?

E.2.2

Secondary objectives of the trial

i) Is folic acid as add-on therapy to antipsychotic treatment more effective than placebo for treatment of positive and negative symptoms of schizophrenia? ii) Is mirtazapine as add-on therapy to antipsychotic treatment more effective than placebo for treatment of negative symptoms of schizophrenia measured on the negative symptoms scale of the PANSS? iii) Is folic acid as add-on therapy to antipsychotic treatment more effective than placebo for treatment of negative symptoms of schizophrenia measured on the negative symptoms scale of the PANSS?

i) La terapia con acido folico in aggiunta alla terapia antipsicotica già in atto è più efficace del placebo nel ridurre i sintomi positivi e negativi della schizofrenia? ii) La terapia con mirtazapina in aggiunta alla terapia antipsicotica già in atto è più efficace del placebo nel ridurre i sintomi negativi della schizofrenia misurati alla scala per i sintomi negativi della PANSS? ii) La terapia con acido folico in aggiunta alla terapia antipsicotica già in atto è più efficace del placebo nel ridurre i sintomi negativi della schizofrenia misurati alla scala per i sintomi negativi della PANSS?

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. diagnosis of DSM-IV schizophrenia; 2. active psychotic symptoms (i.e. hallucinations, delusions, thought disorder); 3. minimum PANSS score 60; 4. inpatient or outpatient; 5. aged 16 to 70 years; 6. able and willing to consent to participate; 7. currently taking effective dose of antipsychotic; 8. clinically appropriate to change or augment treatment; 9. adjunctive mirtazapine appears reasonable and both investigator and patient are uncertain whether it will offer any benefit; 10. not pregnant, breast-feeding or planning a pregnancy; 11. adhering to antipsychotic treatment; 12. drug treatment stable.

1. diagnosi di schizofrenia (DSM-IV); 2. presenza di sintomi psicotici (allucinazioni, deliri, disturbi del pensiero); 3. punteggio minimo alla PANSS di 60; 4. pazienti ambulatoriali e ricoverati; 5. età compresa tra i 16 e i 70 anni; 6. capacità di esprimere la volontà a partecipare allo studio; 7. assunzione di dosi adeguqte di antipsicotico; 8. è clinicamente indicato cambiare la terapia in atto e appare ragionevole poter aggiungere la mirtazapina; 9. non sussistono controindicazioni all'eventuale introduzione dei trattamenti in studio; 10. assenza di gravidanza, allattamento o previsione di gravidanza ; 11. adesione ai trattamenti; 12. trattamento farmacologico stabile.

E.4

Principal exclusion criteria

1. Meeting criteria for current manic episode, including schizoaffective disorder; 2. Current (i.e. within last 2 weeks) antidepressant treatment or considering treatment for depresison; 3. Contraindications to investigational medicinal products. If contraindication is to folic acid only, the patient can be randomised to the mirtazapine/placebo comparison only; 4. Currently taking clozapine.

1. Criteri per un episodio maniacale (incluso il disturbo schizoaffettivo); 2. Attuale trattamento (entro 2 settimane)con antidepressivi o qualora si stia già considerando una terapia antidepressiva per la depressione; 3. Controindicazioni ai farmaci in studio. Se la controindicazione è solo per l'acido folico, il paziente può essere randomizzato solo al confronto mirtazapina/placebo; 4. Attuale trattamento con clozapina. assenza di trattamento con antidepressivo nelle ultime 2 settimane;

E.5 End points

E.5.1

Primary end point(s)

The primary outcome will be reduction in symptoms using the Positive and Negative Syndrome Scale, a 30-item rating scale widely used in assessment of medication effects in schizophrenia (Kay et al., 1987). Kay SR, Fiszbein A & Opler LA. Schizophrenia Bulletin 1987;13(2):261-76

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

12 settimane

E.5.2

Secondary end point(s)

i) Negative symptoms: there is no entirely satisfactory measure of negative symptoms but the PANSS negative subscale has the advantage of being both validated and commonly used (Lieberman et al. 2005; Stahl & Buckley 2007) and can be used to generate quality adjusted life years QALYs, a measure used in health economic evaluation (Rosenheck et al, 2006). ii) Depressive symptoms: the Calgary Depression Scale (Addington, Addington & Maticka-Tyndale 1993) will be used to quantify depressive symptoms. iii) Clinical Impression: the Clinical Global Impression Severity scale (CGI-S) (Guy 1976) will be used to measure overall severity of illness at each baseline and follow-up and the Clinical Global Impression - Improvement scale (CGI-I) will be used at each follow-up visit to rate change from baseline. iv) Akathisia: the Barnes Akathisia Scale (Barnes 1989) will be used to measure akathisia. v) Extra-pyramidal effects: Abbreviated Simpson–Angus scale (SAS) (Simpson & Angus 1970) will be used to measure extra pyramidal symptoms (EPS). vi) Tolerability: tolerability of mirtazapine and of folic acid will be measured by adherence to treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

12 weeks

12 settimane

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

Yes

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

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)

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.4.2

For a multinational trial

F.4.2.1

In the EEA

334

F.4.2.2

In the whole clinical trial

334

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)

No special arrangements are needed because both interventions are avaialable outside the trial. Mirtazapine is available on prescription and participants will be given infomration about over-the-counter vitamin supplements containing folic acid

Non vi è necessità di istituire programmi specifici per il trattamento o l'assistenza per i soggetti al termine della loro partecipazione allo studio, poichè entrambi i trattamenti in studio sono disponibili al fuori dello studio stesso. La mirtazapina può essere prescritta dallo specialista o dal medico di medicina generale attraverso il ricettario regionale; ai partecipanti verranno fornite indicazioni su dove poter reperire eventualmente l'acido folico, come farmaco da banco.

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

2012-10-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-29

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2013-10-19

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