Clinical Trials Register

Summary
EudraCT Number:	2019-002778-30
Sponsor's Protocol Code Number:	GR-2018-12367476
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-01-22
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

2019-002778-30

A.3

Full title of the trial

Efficacy and safety of memantine as antimanic and mood-stabilizing medication for adolescents with Bipolar Disorder: a multi-center, randomized, double-blind, placebo-controlled clinical trial

Efficacia e sicurezza della memantina come farmaco antimaniacale e stabilizzatore dell'umore in adolescenti con Disturbo Bipolare: uno studio multicentrico, randomizzato, in doppio cieco, controllato con placebo

A.3.1

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

Double-blind, randomised, multicenter study to evaluate the efficacy and safety of memantine in adolescents with Bipolar Disorder

Studio multicentrico randomizzato in doppio cieco per valutare l'efficacia e la sicurezza della memantina negli adolescenti con Disturbo Bipolare

A.3.2

Name or abbreviated title of the trial where available

Memantine BD

A.4.1

Sponsor's protocol code number

GR-2018-12367476

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	IRCCS, OSPEDALE PEDIATRICO BAMBINO GESÙ DI ROMA
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	Ministero della Salute
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	Ospedale Pediatrico Bambino Gesù
B.5.2	Functional name of contact point	Neurospichiatria Infantile
B.5.3	Address:
B.5.3.1	Street Address	Piazza Sant’Onofrio 4
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00165
B.5.3.4	Country	Italy
B.5.4	Telephone number	0668592735
B.5.6	E-mail	giulia.serra@opbg.net

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	MEMANTINA ACCORD - 10 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER (PVC/PE/PVDC/ALLUMINIO) - 56 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	ACCORD HEALTHCARE S.L.U.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	MEMANTINA ACCORD
D.3.2	Product code	[NA]
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	MEMANTINA CLORIDRATO
D.3.9.1	CAS number	19982-08-2
D.3.9.2	Current sponsor code	Memantina
D.3.9.4	EV Substance Code	SUB03137MIG
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	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
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 Disorder

Disturbo Bipolare

E.1.1.1

Medical condition in easily understood language

Bipolar Disorder in adolescents

Disturbo bipolare negli adolescenti

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10057667
E.1.2	Term	Bipolar disorder
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

To compare the effect of memantine versus placebo in improving manic symptoms in adolescents meeting standard diagnostic criteria for BD.

Confrontare l'effetto della memantina rispetto al placebo nel migliorare i sintomi maniacali negli adolescenti che soddisfano i criteri diagnostici standard per il disturbo bipolare.

E.2.2

Secondary objectives of the trial

To compare the effect of memantine versus placebo as a mood-stabilizing agent for adolescents with BD.

Confrontare l'effetto della memantina rispetto al placebo come agente stabilizzante dell'umore in adolescenti con disturbo bipolare.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) either sex, aged 13-17 years at baseline;
2) DSM-5 diagnosis of BD (Type I, Type II, Cyclothymic Disorder, Unspecified) with mild to moderate symptom-severity, with current manic, mixed, or hypomanic symptoms (not psychotic) based on expert clinical assessment confirmed with structured diagnostic assessment (with Kiddie-Schedule for Affective Disorders and Schizophrenia for School-aged Children, Present and Lifetime version [K-SADS-PL]);
3) YMRS total score of 20-40 at baseline;
4) CGI-BP severity score of 4-6 at baseline;
5) providing assent to participate and signed consent by a parent or legal representative;
6) girls deemed to be of reproductive potential, must have a confirmed negative urine pregnancy test at intake, and use adequate contraception throughout the study.

1) entrambi i sessi, età compresa tra 13 e 17 anni al baseline;
2) diagnosi secondo il DSM-5 di Disturbo Bipolare (Tipo I, Tipo II, Disturbo Ciclotimico, Non Specificato) con gravità dei sintomi da lieve a moderata, con sintomi maniacali, misti o ipomaniacali (non psicotici) in corso sulla base di una valutazione clinica esperta confermata con valutazione diagnostica strutturata [K-SADS-PL];
3) punteggio totale YMRS di 20-40 al baseline;
4) punteggio di gravità CGI-BP di 4-6 al baseline;
5) che acconsentano a partecipare, e con consenso informato firmato da un genitore o da un rappresentante legale;
6) le ragazze in età riproduttiva devono avere un test di gravidanza urinario negativo confermato all’ingresso nello studio e utilizzare una contraccezione adeguata durante lo studio.

E.4

Principal exclusion criteria

1) YMRS item 8 (delusions; hallucinations) score = 8;
2) exposure to any medicine that can interfere with assessments of safety, tolerability, or efficacy of memantine or placebo, or with the conduct/interpretation of the study; specifically: antipsychotic-antimanic agents including haloperidol, risperidone, quetiapine, aripiprazole, olanzapine, ziprasidone, carbamazepine, lamotrigine, valproate, and antidepressants; ketamine or other NMDA antagonists in last the month prior to enrolment;
3) significant current risk of suicide (in the opinion of the Investigator or a "yes" response to suicidal ideation questions 4 or 5 on the Columbia-Suicide Severity Rating Scale [C-SSRS]) within the last 6 months;
4) intellectual disability (IQ <70), organic mental disorder, or mental disorder due to a general medical condition or substance abuse (DSM-5 criteria);
5) comorbid DSM-5 diagnosis of Substance Abuse Disorder;
6) a serious or unstable general medical illness or clinically significant abnormal vital signs or ECG abnormality;
7) known hypersensitivity to the active substance or to any of the excipients;
8) patient with severe renal impairment (glomerular filtration rate, GFR, < 89 mL/min. GRF 89–60 mL/min: damage with minimal loss of renal function), accoding to Schwartz Equation;
9) patient with severe hepatic impairment: at least one of the following parameters >= 2 ULM (referred to the range of normality of this age group and judged clinically significant by the investigators/ specialist medical consultant and/or needing medical treatment: alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT), bilirubin);
10) patient with serious forms of cardiovascular disease (severe and moderate congenital heart disease: severe and moderate ventricular septal defect, severe and moderate atrial septal defect, Tetralogy of Fallot, complete Transposition of the Great Arteries; severe and moderate valvular stenosis and prolapses; cardiac hypertrophy,), arrhythmias (atrial fibrillation, Paroxysmal supraventricular tachycardia (PSVT), atrial flutter, Wolf-Parkinson-White (WPW), ventricular fibrillation, ventricular tachycardia, Brugada syndrome, severe Sinus bradycardia FC<40 bp/m).

1) punteggio YMRS all’item 8 (deliri, allucinazioni) = 8;
2) esposizione a qualsiasi medicinale che possa interferire con le valutazioni di sicurezza, tollerabilità o efficacia della memantina o del placebo o con la conduzione/interpretazione dello studio (in particolare, agenti antipsicotici-antimaniacali inclusi aloperidolo, risperidone, quetiapina, aripiprazolo, olanzapina, ziprasidone, carbamazepina, lamotrigina, valproato e antidepressivi; ketamina o altri antagonisti NMDA nell’ultimo mese prima dell’arruolamento);
3) significativo rischio attuale di suicidio (secondo il parere dello sperimentatore o risposta "sì" alle domande 4 o 5 sull'ideazione suicidaria della Columbia-Suicide Severity Rating Scale [C-SSRS]) negli ultimi 6 mesi;
4) disabilità intellettiva (QI <70), disturbo mentale organico o disturbo mentale dovuto a una condizione medica generale o abuso di sostanze (secondo i criteri del DSM-5);
5) diagnosi mediante DSM-5 di Disturbo da abuso di sostanze;
6) una condizione medica generale grave o instabile, segni vitali anormali clinicamente significativi o anormalità dell’ECG;
7) ipersensibilità nota al principio attivo o ad uno qualsiasi degli eccipienti;
8) paziente con grave insufficienza renale (velocità di filtrazione glomerulare, GFR, < 89 mL/min. GFR 89-60 mL/min: danno con minima perdita della funzionalità renale), utilizzando l’equazione di Shwartz;
9) pazienti con grave compromissione epatica, con almeno uno dei seguenti parametri >= 2 ULM (riferito al range di normalità di questa fascia di età e giudicato clinicamente significativo dagli sperimentatori/ medici specialisti oppure che richieda trattamento medico: alanino aminotransferasi (ALT), aspartato aminotransferasi (AST), fosfatasi alcalina (ALP) and gamma glutamil transferasi (GGT), bilirubina);
10) paziente con forme gravi di malattia cardiovascolare (cardiopatie congenite gravi e moderate: difetto interventricolare severo o moderato; difetto interatriale severo e moderato, Tetralogia di Fallot, trasposizione dei grossi vasi; stenosi o prolasso valvolare severo o moderato; ipertrofia cardiaca) aritmie (fibrillazione atriale, tachicardia sopraventricolare parossistica (PSVT), flutter atriale, sindrome di Wolf-Parkinson-White (WPW), fibrillazione ventricolare, tachicardia ventricolare, sindrome di Brugada, severa bradicardia sinusale FC<40 bp/m).

E.5 End points

E.5.1

Primary end point(s)

Improvement of manic symptoms by the mean change in YMRS total score from intake to week 12.

Miglioramento dei sintomi maniacali misurato come riduzione media del punteggio totale della YMRS dal reclutamento alla 12esima settimana.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 12 weeks of treatment.

Dopo 12 settimane di trattamento.

E.5.2

Secondary end point(s)

Percentage of subjects showing improvement at the 52-week study as measured by the following outcomes:
a. Percentage of patients completing the 52 weeks of the study in memantine versus placebo group;
b. Significant superior increased C-GAS score in memantine vs placebo group.; Safety and tolerability parameters will be evaluated by recording all adverse events (AEs) and serious adverse events (SAEs).; Time-to-dropout from the AAT phase (days from start of experimental treatment to the start of aripiprazole add-on treatment) in memantine vs placebo arm.; Response of [hypo]manic or mixed episodes by week 12, assessed by evaluating the percentage of subjects given memantine vs placebo showing a response of manic or mixed episodes as reduction by <=50% of the total YMRS score after 12 weeks of treatment.; Percentage of subjects completing the 52-week study and showing remission of symptoms as measured by the combination of the following measures:
a. Percentage of patients with significant improvement of symptoms as measured by CGIBP improvement score <=2
b. Percentage of patients showing response on manic and depressive episodes as measured by a reduction of >=50% at total YMRS score and a reduction of >=50% at total CDRS-R score
c. Percentage of patients showing remission of manic and depressive episodes as defined by a YMRS total score <=12, a CDRS-R total score <=28 and a CGI-BP severity score <=2
d. Percent of patients needing aripiprazole in add-on to the ongoing experimental treatment, average duration of add-on treatment and the average daily dose needed in memantine versus placebo arm during the 52-week study.

Percentuale di soggetti che mostrano un miglioramento alla 52esima settimana dello studio, come misurato dai seguenti outcome:
a. percentuale di pazienti che hanno completato le 52 settimane dello studio nel gruppo con memantina rispetto al gruppo con placebo;
b. aumento significativamente superiore del punteggio C-GAS nel gruppo con memantina rispetto al gruppo con placebo.; I parametri di sicurezza e tollerabilità saranno valutati registrando tutti gli eventi avversi (AE) e gli eventi avversi seri (SAE).; Riduzione dei drop-out dalla fase AAT dovuti alla necessità di terapia in add-on con aripiprazolo per il trattamento di episodi maniacali o misti, misurata come time-to-dropout dalla fase AAT (numero di giorni dall’inizio del trattamento sperimentale fino all’avvio di terapia in add-on con aripiprazolo) nei soggetti trattati con memantina vs placebo.; Risposta degli episodi ipomaniacali, maniacali o misti valutata attraverso la percentuale di soggetti trattati con memantina vs placebo che mostrano una risposta al trattamento negli episodi maniacali o misti intesa come riduzione di <=50% del punteggio totale YMRS dopo 12 settimane di trattamento.; Percentuale di soggetti che completano le 52 settimane di studio e mostrano una remissione dei sintomi come misurata dalla combinazione delle seguenti misure:
a. percentuale di pazienti con un miglioramento significativo dei sintomi misurato con una riduzione dello score della CGI-BP fino ad ottenere un punteggio <= 2;
b. percentuale di pazienti che mostrano una risposta su episodi maniacali e depressivi misurata dalla riduzione di >= 50% al punteggio totale della YMRS e dalla riduzione di >= 50% al punteggio totale della CDRS-R;
c. percentuale di pazienti che mostrano una remissione degli episodi maniacali e depressivi come definito da un punteggio totale YMRS <= 12, un punteggio totale CDRS-R <= 28 e un punteggio di severità CGI-BP <= 2;
d. percentuale di pazienti che necessitano di aripiprazolo in aggiunta al trattamento sperimentale in corso, durata media del trattamento aggiuntivo e dose media giornaliera necessaria nel braccio con memantina vs placebo durante le 52 settimane di studio.

E.5.2.1

Timepoint(s) of evaluation of this end point

At week 52; At week 52; At week 12; After 12 weeks of treatment; At week 52

Alla settimana 52; Alla settimana 52; Alla settimana 12; Dopo 12 settimane di trattamento; Alla settimana 52

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

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.8.6 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

Database lock

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)

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)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Paediatric patients

Pazienti pediatrici

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)

Patients will be treated as per clinical practice.

I pazienti continueranno ad essere trattati secondo la normale pratica clinica.

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

2021-11-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-01-12

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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