Clinical Trials Register

Summary
EudraCT Number:	2017-003074-14
Sponsor's Protocol Code Number:	MYL-1603N-3002
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:	2020-12-15
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

2017-003074-14

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¿ IM versus Placebo IM as an Enhancer Adjunctive to Antidepressant Treatment in Major Depression Disorder Patients Who have not Experienced Sufficient Symptoms Improvement Despite Antidepressant Treatment

Studio multicentrico, randomizzato, in doppio cieco, controllato con placebo, a gruppi paralleli, per confrontare l¿efficacia antidepressiva e la sicurezza di Samyr¿ IM rispetto a placebo IM come stimolatore aggiuntivo alla terapia antidepressiva in pazienti con disturbo depressivo maggiore che non hanno manifestato un miglioramento sufficiente dei sintomi nonostante la terapia antidepressiva

A.3.1

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

A study to evaluate Samyr effectiveness and safety profile. The study is done by comparing that Samyr injection is better than placebo injection in subjects with depression which are treated regularly with antidepressant tablet treatment.

Uno studio per valutare l'efficacia e il profilo di sicurezza di Samyr. Lo studio viene effettuato confrontando che l'iniezione di Samyr ¿ migliore dell'iniezione di placebo in soggetti con depressione trattati regolarmente con il trattamento con compresse antidepressive.

A.3.2

Name or abbreviated title of the trial where available

MYL-1603N-3002

A.4.1

Sponsor's protocol code number

MYL-1603N-3002

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN00000000

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT12345678

A.5.3

WHO Universal Trial Reference Number (UTRN)

U0000-0000-0000

A.5.4

Other Identifiers

Name:

Number:

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	Mylan Inc
B.5.2	Functional name of contact point	David Gillogly
B.5.3	Address:
B.5.3.1	Street Address	Mylan Boulevard, Canonsburg
B.5.3.2	Town/ city	Canonsburg
B.5.3.3	Post code	15317
B.5.3.4	Country	United States
B.5.4	Telephone number	7244856581
B.5.5	Fax number	000000000000
B.5.6	E-mail	David.Gillgly@mylan.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/5 ML POLVERE E SOLVENTE PER SOLUZIONE INIETTABILE 5 FLACONCINI POLVERE + 5 FIALE SOLVENTE 5 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	BGP Products S.r.l
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	SAMYR
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
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	Solution for injection
D.8.4	Route of administration of the placebo	Intramuscular 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 Disorders

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 Samyr IM is superior to placebo IM as an enhancer adjunctive to antidepressant therapy.
The primary endpoint is the change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) for Depression score after 7 days (visit 13) of treatment.

Dimostrare che Samyr formulazione intramuscolare ¿ superiore al placebo formulazione intramuscolare come stimolatore aggiuntivo alla terapia antidepressiva.
L¿endpoint primario ¿ la variazione del punteggio di depressione nella Scala di valutazione della depressione di Montgomery Asberg (MADRS) tra il basale e la Visita 13, a 7 giorni dall¿inizio del trattamento.

E.2.2

Secondary objectives of the trial

To compare mean change from baseline to day 14 (visit 20) for MADRS, Hamilton Depression Rating Scale (HDRS)-6, Patient Global Impression (PGI) scale and Clinical Global Impression (CGI) scale between the 2 treatments.

To evaluate the safety and tolerability of Samyr IM.

Confrontare la variazione media dal basale al Giorno 14 (Visita 20) nella MADRS, nella Scala di valutazione della depressione di Hamilton (HDRS)-6, nella scala relativa all¿Impressione globale del paziente (PGI) e nella scala relativa all¿Impressione clinica globale (CGI) tra i 2 trattamenti.

Valutare la sicurezza e la tollerabilit¿ di Samyr formulazione intramuscolare.

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), criteria.
5. Subject is on prescribed SSRI (citalopram / escitalopram / sertraline / paroxetine) or SNRI (venlafaxine / duloxetine) antidepressant treatment, at approved and stable dose (based on local SmPC), for at least 4 weeks prior to screening.
6. Partial-response to the prescribed antidepressant during the last 8 weeks prior to screening. Partial response is defined as less than 50% symptom reduction.
7. Subject who have a Montgomery-Asberg Depression Rating Scale (MADRS) score as assessed by the site investigator of at least 22 at screening and with less than 15% reduction at baseline, post run in treatment.

Per risultare idonei all’arruolamento nello studio, i soggetti devono soddisfare tutti i criteri di inclusione elencati di seguito:
1. Il soggetto deve fornire il consenso informato scritto e firmato prima di iniziare una qualsiasi delle procedure specifiche del protocollo.
2. Soggetti di ambo i sessi di età compresa tra 18 e 65 anni, entrambe le età incluse.
3. Il soggetto deve essere disposto e in grado di attenersi ai requisiti del protocollo dello studio, compresi il programma delle visite, le valutazioni e le scale.
4. Diagnosi primaria di disturbo depressivo maggiore (DDM) della durata di almeno 12 settimane, in base ai criteri definiti nel Manuale statistico e diagnostico dei disturbi mentali, quinta edizione (DSM 5).
5. Il soggetto assume, dietro prescrizione, una terapia antidepressiva con SSRI (citalopram/escitalopram/sertralina/paroxetina) o SNRI (venlafaxina/duloxetina) a una dose stabile e approvata (in base al Riassunto delle caratteristiche del prodotto [RCP] locale) da almeno 4 settimane prima dello screening.
6. Risposta parziale alla terapia antidepressiva prescritta durante le ultime 8 settimane precedenti lo screening. La risposta parziale è definita come una riduzione dei sintomi <50%.
7. Il soggetto presenta un punteggio della Scala di valutazione della depressione di Montgomery-Asberg (MADRS), valutato dallo sperimentatore del centro, di almeno 22 allo screening e una riduzione <15% al basale dopo il trattamento preliminare.

E.4

Principal exclusion 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. History of bipolar disorders, Schizophrenia and other psychotic disorders.
6. Substance abuse or dependence.
7. Previous suicidal planning or suicide attempt.
8. Use of more than 4 acceptable antidepressant treatments since the diagnosis of depression or treatment with ECT or ketamine during the current episode or lifetime treatment with Vagus Nerve Stimulation (VNS) during the last 5 years.
9. Previous treatment with Samyr which was not effective or resulted in an AE, or already treated with Samyr during the current episode.
10. Hypersensitivity to the active substance or to any of the excipients of Samyr.
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.
14. Treatment with at least one prohibited medication as detailed in Appendix 1 (prohibit drug medication prior and during the study).
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. 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. Subject did not pass the remote assessment with MGH CTNI rater.
20. Decrease in the baseline MADRS score by = 15% vs screening visit.
21. Female subjects who are pregnant or plan to be pregnant or breast feeding.
22. 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.

1. Anamnesi o presenza di condizione medica o malattia che, secondo l’opinione dello sperimentatore, potrebbe esporre il soggetto a un rischio inaccettabile a seguito della partecipazione alla sperimentazione.
2. Qualsiasi anomalia clinicamente significativa nell’elettrocardiogramma (ECG) o nelle analisi di laboratorio di sicurezza che, a parere dello sperimentatore, esporrebbe il soggetto a un rischio inaccettabile a seguito della partecipazione alla sperimentazione.
3. Assunzione di un altro farmaco sperimentale nei 45 giorni precedenti lo screening o collocazione temporale della visita di screening entro 5 emivite di un altro farmaco sperimentale ricevuto (a seconda di quale sia il periodo di tempo più lungo), oppure previsione di ricevere un altro farmaco sperimentale durante il periodo dello studio in corso.
4. Qualsiasi intervento chirurgico elettivo che richieda il ricovero programmato durante il periodo dello studio.
5. Anamnesi di disturbo bipolare, schizofrenia e altri disturbi psicotici.
6. Abuso o dipendenza da sostanze stupefacenti.
7. Precedente pianificazione suicidaria o tentativo di suicidio.
8. Uso di più di 4 trattamenti antidepressivi accettabili dalla diagnosi di depressione oppure trattamento con terapia elettroconvulsiva (TEC) o ketamina durante l’episodio attuale o trattamento permanente con stimolazione del nervo vago (SNV) durante gli ultimi 5 anni.
9. Precedente trattamento con Samyr che non sia risultato efficace o abbia comportato un EA, oppure trattamento in corso con Samyr durante l’episodio attuale.
10. Ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti di Samyr.
11. Soggetti con difetti genetici noti che influenzano il ciclo della metionina e/o causano omocistinuria e/o iperomocisteinemia (ad es. carenza di cistationina beta-sintetasi, difetti del metabolismo della vitamina B12).
12. Trattamento con inibitori delle monoamino ossidasi (MAO), inclusi selegilina e moclobemide, durante le 4 settimane precedenti lo screening.
13. Trattamento con linezolid o pimozide.
14. Trattamento con almeno un farmaco proibito tra quelli indicati nell’Appendice 1 (trattamenti farmacologici proibiti prima e durante lo studio).
15. Patologia cardiaca che, secondo l’opinione dello sperimentatore, potrebbe esporre il soggetto a un rischio inaccettabile a seguito della partecipazione alla sperimentazione.
16. Prolungamento noto dell’intervallo QT o sindrome congenita del QT lungo.
17. Trattamento con prodotti che sono noti per prolungare l’intervallo QT.
18. Valori epatici che, secondo l’opinione dello sperimentatore, potrebbero esporre il soggetto a un rischio inaccettabile a seguito della partecipazione alla sperimentazione.
19. Mancato superamento della valutazione da remoto del soggetto con il valutatore del Massachusetts General Hospital’s Clinical Trials Network and Institute (MGH CTNI).
20. Diminuzione nel punteggio MADRS basale di =15% rispetto alla visita di screening.
21. Soggetti di sesso femminile in stato di gravidanza o che prevedono di avviare una gravidanza o in fase di allattamento al seno.
22. Soggetti di sesso femminile in età fertile che non sono disposte o in grado di utilizzare contraccettivi orali o metodi di contraccezione accettabili tra quelli descritti nel presente protocollo (Sezione 4.3), a partire dallo screening e per tutta la durata dello studio, fino al suo completamento.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in the MADRS score after 7 days of treatment (visit 13)

Variazione rispetto al basale nel punteggio MADRS dopo 7 giorni di trattamento (Visita 13)

E.5.1.1

Timepoint(s) of evaluation of this end point

7 days

7 giorni

E.5.2

Secondary end point(s)

Change from baseline in the MADRS score after 14 days of treatment (visit 20); Change from baseline of the HDRS-6, PGI and CGI scales after 7 and 14 days of treatment (visits 13 and 20)

Variazione rispetto al basale nel punteggio MADRS dopo 14 giorni di trattamento (Visita 20).; Variazione rispetto al basale nelle scale HDRS-6, PGI e CGI dopo 7 e 14 giorni di trattamento (Visite 13 e 20)

E.5.2.1

Timepoint(s) of evaluation of this end point

after 14 days; after 7 and 14 days of treatment

dopo 14 giorni; dopo 7 e 14 giorni di trattamento

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

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.8.5.1

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

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:

468

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

468

F.4.2

For a multinational trial

F.4.2.1

In the EEA

468

F.4.2.2

In the whole clinical trial

468

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 doctor

Una volta che la materia entra nello studio, il soggetto sar¿ trattato con il farmaco in studio e anche con il trattamento prescritto dal medico in questione prima di entrare nello studio. Una volta che il soggetto completa lo studio (completa lo studio o si interrompe anticipatamente o ha perso il follow-up) il soggetto continuer¿ con il trattamento fornito dal suo 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

2018-09-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-19

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

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