Clinical Trials Register

Summary
EudraCT Number:	2013-002055-15
Sponsor's Protocol Code Number:	J81J1100168007
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:	2013-09-13
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

2013-002055-15

A.3

Full title of the trial

RANDOMIZED, CONTROLLED, MULTI-CENTER, INTERNATIONAL CLINICAL
STUDY ON THE MOOD-STABILIZING EFFECTS OF MEMANTINE AS AN AUGMENTING AGENT vs. LAMOTRIGINE FOR ONGOING TREATMENT IN
BIPOLAR-I DISORDER PATIENTS RESISTANT TO TREATMENT WITH LITHIUM AND/OR OTHER MOOD-STABILIZERS

STUDIO CLINICO , MULTICENTRICO, INTERNAZIONALE, RANDOMIZZATO, CONTROLLATO SULLA PREVENZIONE DI RICADUTE DEPRESSIVE O MANIACALI DELLA MEMANTINA (“AS AUGMENTING AGENT”), vs. LAMOTRIGINA NEI DISTURBI BIPOLARI RESISTENTI AL TRATTAMENTO CON SALI DI LITIO E/O ALTRI STABILIZZANTI.

A.3.1

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

CONTROLLED MULTICENTER STUDY ON THE MOOD-STABILIZING EFFECT OF MEMANTINE IN BIPOLAR I DISORDERS

STUDIO MULTICENTRICO CONTROLLATO SULL'EFFETTO PROFILATTICO DELLA MEMANTINA NEL DISTURBO BIPOLARE DI TIPO I

A.3.2

Name or abbreviated title of the trial where available

MEMANTINE AS A MOOD-STABILIZER

MEMANTINA NELLA PROFILASSI DELLA MALATTIA MANIACO-DEPRESSIVA

A.4.1

Sponsor's protocol code number

J81J1100168007

A.5.4

Other Identifiers

Name:

MEMANTINE AND BIPOLAR DISORDERS

Number:

MEMANTINA E MALATTIA MANIACO-DEPRESSIVA

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 SASSARI
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	UNIVERSITY OF SASSARI
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	UNIVERSITY OF SASSARI
B.5.2	Functional name of contact point	GINO SERRA
B.5.3	Address:
B.5.3.1	Street Address	DIPARTIMENTO DI SCIENZE BIOMEDICHE, VIALE SAN PIETRO, 43
B.5.3.2	Town/ city	SASSARI
B.5.3.3	Post code	07100
B.5.3.4	Country	Italy
B.5.4	Telephone number	00393290092278
B.5.5	Fax number	0039079228715
B.5.6	E-mail	dsfserra@uniss.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	EBIXA
D.2.1.1.2	Name of the Marketing Authorisation holder	H. Lundbeck A/S
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.3.4	Pharmaceutical form	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	MEMANTINE
D.3.9.1	CAS number	19982-08-2
D.3.9.4	EV Substance Code	SUB08731MIG
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	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	Comparator
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	LAMOTRIGINE DOC -GENERIC
D.2.1.1.2	Name of the Marketing Authorisation holder	DOC Generici Srl, via Manuzio 7, 20124 Milano
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.3.4	Pharmaceutical form	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	N03AX09
D.3.9.3	Other descriptive name	LAMOTRIGINE
D.3.9.4	EV Substance Code	SUB08393MIG
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	200
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

BIPOLAR I MOOD DISORDERS

DISTURBO DELL'UMORE DI TIPO I

E.1.1.1

Medical condition in easily understood language

MANIC-DEPRESSIVE ILLNESS

MALATTIA MANIACO-DEPRESSIVA

E.1.1.2

Therapeutic area

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

MedDRA Classification

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 study will compare effect of adding, by random selection, memantine or lamotrigine, to the ongoing mood-stabilizer treatment of bipolar disorder patients who have not been adequately stabilized during
at least two years of adequate trials of standard mood-stabilizers: lithium, anticonvulsants, or modern antipsychotics, alone or in various combinations. Ongoing mood-stabilizer treatments will be held constant during the proposed one-year trial. Lamotrigine is selected as the study
comparator since it is the only anticonvulsant medication approved by the US Food and Drug Administration for long-term prevention of recurrences of all phases of bipolar I disorder.

Lo studio intende paragonare l'effetto dell'aggiunta, in modo randomizzato, di di stabilizzanti dell'umore: litio, anticonvulsivanti, o antipsicotici atipici, in monoterapia o in varie memantina e di lamotrigina, alla terapia stabilizzante in atto di pazienti bipolari che non sono stati stabilizzati adeguatamente durante I due anni precedenti con la somministrazione di dosi adeguate combinazioni. I trattamenti in atto verranno mantenuti inalterati per tutta la durata dell'anno dello studio. La Lamotrigina è stat scelta come comparatore perchè è l'unico anticonvulsivante approvato dalla Food and Drug Administration per la prevenzione/profilassi a lungo termine delle ricadute sia maniacali sia depressive del disturbo bipolre di tipo I.

E.2.2

Secondary objectives of the trial

NOT APPLICABLE

NON APPLICABILE

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Diagnosis of Bipolar Disorder type I (according to DSM-IV TR criteria)

2. Having been in long-term treatment with lithium (plasma levels ≥0.5
mEq/L) or other mood stabilizers ( Carbamazepine, Valproate or Atypical
Antipsychotics, administred at standard daily dose) or their
combinations for at least two years at standard therapeutic doses.

3. Showing inadequate response to mood-stabilizers defined by the
occurrence of at least two episodes of illness defined by DSM-IV TR
criteria and supported by depression (MADRS) and mania (YMRS)
ratings, as follows: one or more major depressive episodes with one or
more MADRS scores >20; one or more manic/hypomanic episodes with
one or more YMRS scores >12; or one or two more mixed episodes with
elevated ratings as already defined), and persisting for a total of at least
6 months per year in the previous 24 months of sustained treatment.

1. Diagnosi di disturbo bipolare di tipo I (secondo DSM-IV TR)
2. Trattamento a lungo termine con sali di litio (livelli plasmatici ≥ 0,5 mEq/L) o con altri stabilizzatori dell'umore (carbamazepina, valproato o antipsicotici atipici, somministrati alle dosi standard giornaliere) o loro combinazioni per almeno due anni a dosi terapeutiche standard.
3. Risposta inadeguata a stabilizzatori dell'umore definita dalla presenza di almeno due episodi di malattia secondo i criteri DSM-IV TR e supportata da scale di valutazione della depressione (MADRS) e della episodi misti con punteggi alle scale come già definiti, e la persistenza di malattia per un totale di almeno 6 mesi all'anno negli ultimi 24 mesi.mania (YMRS), come segue: uno o più episodi depressivi maggiori con uno o più punteggi alla MADRS > 20; uno o più episodi maniacali/ipomaniacali con uno o più punteggi alla YMRS > 12

E.4

Principal exclusion criteria

1.Patients with suspected or known hypersensitivity to the study drugs.
2.Fertile women not taking contraceptives, pregnant or breastfeeding.
3.Patients who have already received the drugs under study within 24
previous months.
4.Patients with clinically significant, active medical illness or abnormal
thyroid (TSH) or renal (creatinine) tests.
5.Patients with clinically significant EKG abnormalities.
6. Patients with a history of epileptic seizures or current EEG
abnormalities.
7.Patients meeting DSM-IV-TR criteria for a substance-use disorder
within the previous 24 months and with currently positive screening
assays of urine and blood for commonly abused substances.

1. Sospetta o nota ipersensibilità ai farmaci utilizzati nello studio.
2. Donne in età fertile che non assumono contraccettivi, in gravidanza o allattamento.
3. Pazienti che hanno già ricevuto i farmaci oggetto dello studio entro i 24 mesi precedenti.
4. Altre malattie mediche clinicamente significative e attive o patologie della tiroide (TSH) o renali (test della creatinina).
5. Anomalie clinicamente significative all’ECG.
6. Storia di attacchi epilettici o con anomalie all’EEG in atto.
7. Pazienti che soddisfano i criteri DSM-IV-TR per abuso di sostanze nei precedenti 24 mesi e con test di screening di urine e sangue attualmente positivi per le sostanze più comunemente abusate.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoints (within 52 weeks):
1. Reduction from the previous 24 months of the number and total
weeks of manic/hypomanic, depressive or mixed recurrences, based on
clinical assessments to ascertain DSM-IV-TR diagnostic criteria, as well
as use of averaged ratings (up to 52/patient) of YMRS, MADRS, and CGIBP
(CGI-BP-Severity, CGI-BP-Improvement) scores.

2. Latency (weeks) from the start of experimental treatment to
emergence of a first new episode (recurrence) of illness.

1. Riduzione rispetto ai precedenti 24 mesi del numero e della durata in settimane totali degli episodi maniacali/ipomaniacali, depressivi o misti, sulla base della valutazione clinica in accordo ai criteri diagnostici DSM-IV-TR, così come dei punteggi medi (fino a 52/paziente) alle scale YMRS e MADRS e CGI-BP (CGI-BP-Severity, CGI-BP-Improvement).
2. Latenza (settimane) dall'inizio del trattamento sperimentale alla comparsa di un primo nuovo episodio (recidiva) di malattia.

E.5.1.1

Timepoint(s) of evaluation of this end point

52 weeks

52 settimane

E.5.2

Secondary end point(s)

Additional data to be considered include: sex, age, marital status,
educational level and occupation, as well as diagnosis, age at onset,
polarity of first-lifetime episode, illness duration, total number of
episodes and their polarity per year of illness, and psychiatric family
history. Secondary endpoints will include the total and average mg/day
doses of each psychotropic agent employed during the one-year
protocol.

I dati riguardanti l’outcome primario saranno confrontati con covariate di rilievo di tipo demografico e clinico: sesso, eta, stato civile, livello di istruzione e occupazione, diagnosi, eta di
esordio, polarita del primo episodio, durata della malattia, numero totale di episodi e loro polarita per anno di malattia e storia familiare psichiatrica. Gli endpoints secondari includono la dose totale e media (mg/die) di ciascun agente psicotropo utilizzata durante l’anno di protocollo.

E.5.2.1

Timepoint(s) of evaluation of this end point

52 weeks

52 settimane

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

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

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

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

E.8.7

Trial has a data monitoring committee

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

ULTIMA VISITA ULTIMO SOGGETTO

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.1.1.1

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:

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

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

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

106

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)

RESPONDER PATIENTS COULD CONTINUE, WITH OUR CONSENT, THE MOOD-STABILIZING THERAPY

I PAZIENTI STABILIZZATI POTRANNO, COL LORO CONSENSO, CONTINUARE LA TERAPIA STABILIZZANTE

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

2013-12-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-28

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

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