Clinical Trials Register

Summary
EudraCT Number:	2017-003073-33
Sponsor's Protocol Code Number:	MYL-1603N-3001
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:	2023-07-05
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

2017-003073-33

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-Center Study to Compare the Anti-Depressive Efficacy and Safety of Samyr® Tablet versus Placebo Tablet on top of Adjunctive Antidepressant Treatment in Patients with Major Depression Disorder with Mild to Moderate Symptoms

Studio randomizzato, in doppio cieco, controllato con placebo, a gruppi paralleli, multicentrico volto a confrontare l’efficacia antidepressiva e la sicurezza di Samyr® compresse rispetto alle compresse di placebo in aggiunta al trattamento antidepressivo supplementare in pazienti con disturbo depressivo maggiore con sintomi da lievi a moderati

A.3.1

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

A research study to compare the antidepressant ability and safety of Samyr® tablets versus placebo tablets as an adjunct to additional antidepressant treatment in patients with major depressive disorder (MDD)

Uno studio di ricerca per confrontare l'abilità antidepressiva e la sicurezza delle compresse di Samyr® rispetto alle compresse di placebo in aggiunta al trattamento con antidepressivi aggiuntivo nei pazienti con disturbo di depressione maggiore (MDD)

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

MYL-1603N-3001

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	Mylan 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	Mylan 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	Meda Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	Melanie Emmeluth
B.5.3	Address:
B.5.3.1	Street Address	Benzstrasse 1
B.5.3.2	Town/ city	Bad Homburg
B.5.3.3	Post code	D-61352
B.5.3.4	Country	Germany
B.5.4	Telephone number	00491726300495
B.5.5	Fax number	000000
B.5.6	E-mail	melanie.emmeluth@viatris.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	SAMYR - 400 MG COMPRESSE GASTRORESISTENTI20 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	Mylan Italia Srl
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.3.1	Product name	Samyr
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Gastro-resistant 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	S ADENOSIL L METIONINA 1,4 BUTANDISOLFONATO
D.3.9.2	Current sponsor code	Ademetionine 1,4-butandisulfonate oral grade
D.3.9.3	Other descriptive name	Ademetionine SD4, SAMe SD4, Ade-SD4, SAMe 1,4butanedisulfonate,AdometSD4,activemethionine SD4
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	800 to 1600
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	Gastro-resistant 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

Major Depression Disorder

Disturbo Depressivo Maggiore

E.1.1.1

Medical condition in easily understood language

Major Depression

Depressione maggiore

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	10057840
E.1.2	Term	Major depression
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 demonstrate that in subjects with MDD with inadequate response to antidepressants and Hamilton score of 15-20 (with up to 10% reduction at baseline) Samyr® is superior to placebo tablet, when used along with an adjunctive antidepressant therapy following six weeks of treatment based on HDRS-17 score

Dimostrare che, nei soggetti con disturbo depressivo maggiore (MDD) con risposta inadeguata agli antidepressivi and con punteggio Hamilton di 15-20 (con fino al 10% di riduzione al basale) Samyr® risulta superiore alla compressa di placebo quando usato in aggiunta a una terapia antidepressiva dopo sei settimane di trattamento sulla base del punteggio HDRS-17

E.2.2

Secondary objectives of the trial

Secondary objective:
To evaluate the general improvement on the Patient Global Impression (PGI) scale and the Clinical Global Impression (CGI) scale following six weeks of treatment.
Safety objective:
To evaluate the safety and tolerability of Samyr® tablet

Obiettivo secondario:
Valutare il miglioramento generale sulla scala Patient Global Impression (PGI) e sulla scala Clinical Global Impression (CGI) dopo sei settimane di trattamento.
Obiettivo di sicurezza:
Valutare la sicurezza e la tollerabilità di Samyr® compresse

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all the following inclusion criteria to be eligible for enrolment into the study:
1. Written and signed informed consent needs to be provided by subject before starting any protocol-specific procedures.
2. Male and female subject between the ages of 18 to 65 years, both ages inclusive.
3. Subject who is able and willing to comply with the requirements of the study protocol including the visits scheme, assessments and scales.
4. Primary diagnosis of MDD of at least 12 weeks duration, according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and as confirmed by version 7.0 of the Mini International Neuropsychiatric Interview (MINI).
5. Subject is on prescribed SSRI (citalopram / escitalopram / sertraline / paroxetine / fluoxetine) or SNRI (venlafaxine / desvenlafaxine / duloxetine) antidepressant treatment, at approved and stable dose, for at least 4 weeks prior to screening that is insufficient/ineffective.
6. The subject is deemed to have inadequate response (less than 50% symptom reduction) to their current antidepressant based on the investigator judgment and the treatment history.
7. Subject who have a HDRS-17 score between 15-20 at screening. The baseline score must remain =20 and should not have >10% reduction between screening and baseline (randomization visit).

Per essere idonei all’arruolamento nello studio, i soggetti devono soddisfare tutti i seguenti criteri di inclusione:
1. Il soggetto deve fornire un consenso informato scritto e firmato prima di iniziare qualsiasi procedura specifica dello studio.
2. Soggetti di sesso maschile e femminile di età compresa tra 18 e 65 anni inclusi.
3. Il soggetto deve essere in grado e disposto a rispettare i requisiti del protocollo dello studio, compresi lo schema delle visite, le valutazioni e le scale.
4. Diagnosi primaria di MDD di durata minima di 12 settimane, in base al Manuale diagnostico e statistico dei disturbi mentali, quinta edizione (DSM-5) e confermata in base alla versione 7.0 della Mini-intervista neuropsichiatrica internazionale (MINI).
5. Il soggetto sta assumendo un trattamento antidepressivo insufficiente/inefficace con prescrizione di SSRI (citalopram/escitalopram/sertralina/paroxetina/fluoxetina) o di SNRI (venlafaxina/desvenlafaxina/duloxetina), a una dose approvata e stabile, da almeno 4 settimane precedenti allo screening.
6. Si ritiene che il soggetto abbia una risposta inadeguata (riduzione dei sintomi inferiore al 50%) all’antidepressivo attuale, sulla base del giudizio dello sperimentatore e dell’anamnesi del trattamento.
7. Il soggetto deve avere un punteggio di HDRS-17 compreso tra 15 e 20 allo screening. Il punteggio al basale deve rimanere = 20 e non deve far osservare una riduzione > 10% tra lo screening e il basale (visita di randomizzazione).

E.4

Principal exclusion criteria

Subject must not be enrolled in the study if they meet any of the following criteria:
1. History or presence of a medical condition or disease that in the Investigator’s opinion would place the subject at an unacceptable risk as a result of trial participation.
2. Any clinically significant abnormality in electrocardiogram (ECG) or safety laboratory tests that in the Investigator’s opinion would place the subject at an unacceptable risk as a result of trial participation.
3. Receipt of another investigational drug within 45 days prior to screening, or if the screening visit is within 5 half-lives of another investigational drug received (whichever is longer) or scheduled to receive another investigational drug during the current study period.
4. Any elective surgery requiring hospitalization planned during the study period.
5. Any lifetime history of bipolar disorders or psychotic disorders (other than MDD with psychotic features in a prior but not the current episode) as per the MINI.
6. History of drug abuse and/or marijuana use and/or alcohol dependence during the 3 years prior to screening.
7. The subject is, in the investigator’s opinion, at significant current risk of harming himself/herself, or provides the following answers on the C-SSRS at screening:
• “Yes” to Question 4 or 5 on the Lifetime version Suicidal Ideation section and the ideation was within the last 3 months at Screening Visit, OR
• “Yes” to question on the Lifetime version Suicidal Behavior section (other than preparatory behavior) and the ideation was within the last 3 months at Screening Visit.
8. Use of more than any 4 acceptable antidepressant treatments since the diagnosis of depression.
9. Previous treatment with Samyr which was not effective or resulted in an AE, or already treated with Samyr for the current episode.
10. Hypersensitivity to the active substance or to any of the excipients of Samyr or placebo (lactose).
11. Subjects with known genetic defects which affect the methionine cycle and/or cause homocystinuria and/or hyperhomocysteinaemia (e.g. cystathionine beta-synthase deficiency, defects of vitamin B12 metabolism).
12. Treatment with Monoamine Oxidase (MAO)-inhibitors including selegiline and moclobemide, during the 4 weeks prior to screening.
13. Treatment with linezolid or pimozide during the 4 weeks prior to screening; these must not be taken during study.
14. Treatment with prohibit medication prior to screening as detailed in Appendix 1.
15. Cardiac disorder which in the Investigator’s opinion would place the subject at an unacceptable risk from trial participation.
16. Known QT interval prolongation or congenital long QT syndrome.
17. Currently treatment with products that are known to prolong the QT interval.
18. Hepatic values that in the Investigator’s opinion would place the subject at an unacceptable risk as a result of trial participation.
19. Female subjects who are pregnant or breast-feeding or are planning to become pregnant during the study.
20. Female subjects of childbearing potential who are not able/willing to use oral contraception or acceptable methods of contraception as outlined in this protocol (Section 4.3), from the time of screening and for the duration of the study, through study completion.

Il soggetto non deve essere arruolato nello studio se soddisfa uno dei seguenti criteri:
1. Anamnesi o presenza di una condizione medica o patologia che, secondo l’opinione dello sperimentatore, presenterebbe un rischio inaccettabile per il soggetto come conseguenza della partecipazione alla sperimentazione.
2. Qualsiasi anomalia clinicamente significativa nell’elettrocardiogramma (ECG) o negli esami di laboratorio di sicurezza che, secondo l’opinione dello sperimentatore, presenterebbe un rischio inaccettabile per il soggetto come conseguenza della partecipazione alla sperimentazione.
3. Assunzione di un altro farmaco sperimentale entro i 45 giorni precedenti lo screening o se la visita di screening avviene entro 5 emivite di un altro farmaco sperimentale assunto (a seconda di quale periodo sia più lungo), oppure assunzione programmata di un altro farmaco sperimentale durante il periodo dello studio attuale.
4. Qualsiasi intervento chirurgico elettivo che richieda il ricovero, programmato durante il periodo dello studio.
5. Qualsiasi anamnesi a lungo termine di disturbi bipolari o psicotici (diversi dalla MDD con caratteristiche psicotiche in un episodio precedente ma non in quello corrente) in base alla MINI.
6. Anamnesi di abuso di droghe e/o uso di marijuana e/o dipendenza da alcol durante i 3 anni precedenti allo screening.
7. Il soggetto è, secondo l’opinione dello sperimentatore, ad attuale rischio significativo di autolesionismo o fornisce le seguenti risposte al questionario della Scala della Columbia University per la valutazione della gravità del rischio di suicidio (C-SSRS) allo screening:
• “Sì” alla Domanda 4 o 5 nella versione Nel Corso della vita della sezione Ideazione suicidaria e l’ideazione si è manifestata negli ultimi 3 mesi alla Visita di screening, OPPURE
• “Sì” alla domanda nella versione Nel Corso della vita della sezione Comportamento suicidario (diverso dal comportamento preparatorio) e l’ideazione si è manifestata negli ultimi 3 mesi alla Visita di screening.
8. Uso di più di 4 trattamenti antidepressivi accettabili dalla diagnosi di depressione.
9. Trattamento precedente con Samyr che è risultato inefficace o ha provocato un EA, oppure episodio corrente già trattato con Samyr.
10. Ipersensibilità al principio attivo o a uno degli eccipienti di Samyr o al placebo (lattosio).
11. Soggetti con difetti genetici noti che influenzano il ciclo della metionina e/o provocano omocistinuria e/o iperomocisteinemia (ad esempio, carenza di cistationina beta-sintasi, difetti del metabolismo della vitamina B12).
12. Trattamento con inibitori delle monoamino-ossidasi (MAO), comprese selegilina e moclobemide, durante le 4 settimane precedenti lo screening.
13. Trattamento con linezolid o pimozide durante le 4 settimane precedenti lo screening; questi farmaci non devono essere presi durante lo studio.
14. Trattamento con un farmaco vietato prima dello screening, come indicato nell’Appendice 1.
15. Disturbo cardiaco che, secondo l’opinione dello sperimentatore, presenterebbe un rischio inaccettabile per il soggetto come conseguenza della partecipazione alla sperimentazione.
16. Prolungamento dell’intervallo QT o sindrome congenita del QT lungo noti.
17. Attuale trattamento con prodotti noti per prolungare l’intervallo QT.
18. Valori epatici che, secondo l’opinione dello sperimentatore, presenterebbero un rischio inaccettabile per il soggetto come conseguenza della partecipazione alla sperimentazione.
19. Soggetti di sesso femminile in gravidanza o in allattamento o che stanno pianificando una gravidanza durante lo studio.
20. Soggetti di sesso femminile in età fertile che non sono in grado/disposte a usare la contraccezione orale o i metodi contraccettivi accettabili delineati nel presente protocollo (Sezione 4.3), dal momento dello screening e per tutta la durata dello studio, fino al completamento dello stesso.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in the HDRS-17 score after 6 weeks of treatment (visit 9)

Variazione dal basale del punteggio nella HDRS-17 dopo 6 settimane di trattamento (visita 9)

E.5.1.1

Timepoint(s) of evaluation of this end point

After 6 weeks of treatment (visit 9)

6 settimane dopo il trattamento (visita 9)

E.5.2

Secondary end point(s)

Change from baseline of the PGI and CGI scales after 6 weeks of treatment (visit 9)

Variazione dal basale delle scale PGI e CGI dopo 6 settimane di trattamento (visita 9)

E.5.2.1

Timepoint(s) of evaluation of this end point

After 6 weeks of treatment (visit 9)

6 settimane dopo il trattamento (visita 9)

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

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.1.1.1

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:

600

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

600

F.4.2

For a multinational trial

F.4.2.1

In the EEA

600

F.4.2.2

In the whole clinical trial

600

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)

Once subject enters the study, the subject will be treated with the study drug and also with the treatment prescribed by the subject doctor before entering the study. Once subject completes the study (complete the study or early terminate or lost to follow up) the subject will continue with the treatment provided by his/her doctor

Una volta che il soggetto entra nello studio, il soggetto sarà trattato con il farmaco in studio e anche con il trattamento prescritto dal medico del soggetto prima di entrare nello studio. Una volta che il soggetto ha completato lo studio (completato lo studio o terminato anticipatamente o perso al follow-up) il soggetto continuerà con il trattamento fornito dal proprio medico

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

2022-11-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-03-08

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

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