Clinical Trials Register

Summary
EudraCT Number:	2018-004145-16
Sponsor's Protocol Code Number:	Z7219K01
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-06-11
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

Spain - AEMPS

A.2

EudraCT number

2018-004145-16

A.3

Full title of the trial

A 12-weeks, multicentre, randomized, double-blind, placebo-controlled, exploratory, pilot study to evaluate the safety and efficacy of safinamide 200 mg once daily, as add-on therapy, in patients with possible or probable parkinsonian variant of multiple system atrophy.

Estudio piloto, exploratorio, multicéntrico, aleatorizado, doble ciego y controlado por placebo de 12 semanas de duración para evaluar la seguridad y la eficacia de Safinamida 200 mg una vez al día, como tratamiento complementario, en pacientes con posible o probable variante parkinsoniana de Atrofia Multi-Sistémica.

A.3.1

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

A study evaluating the safety and efficacy of safinamide for patients with Multiple System Atrophy

Estudio para evaluar la seguridad y eficacia de Safinamida en pacientes con Atrofia Multi-Sistémica

A.3.2

Name or abbreviated title of the trial where available

Safinamide for Multiple System Atrophy

A.4.1

Sponsor's protocol code number

Z7219K01

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	Zambon SpA
B.1.3.4	Country	Italy
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	Zambon SpA
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	Zambon SpA
B.5.2	Functional name of contact point	Clinical Development
B.5.3	Address:
B.5.3.1	Street Address	Via Lillo del Duca 10
B.5.3.2	Town/ city	Bresso, Milan
B.5.3.3	Post code	20091
B.5.3.4	Country	Italy
B.5.4	Telephone number	+3902665241
B.5.6	E-mail	clinicaltrials@zambongroup.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	Xadago
D.2.1.1.2	Name of the Marketing Authorisation holder	Zambon SpA
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.3.4	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	safinamide methanesulfonate
D.3.9.1	CAS number	133865-89-1
D.3.9.3	Other descriptive name	SAFINAMIDE
D.3.9.4	EV Substance Code	SUB32946
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	100
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	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

Parkinsonian variant of Multiple System Atrophy

variante parkinsoniana de atrofia multisistémica

E.1.1.1

Medical condition in easily understood language

Multiple System Atrophy

atrofia multisistémica

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10064060
E.1.2	Term	Multiple system atrophy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety and tolerability of safinamide, 200 mg od, compared with placebo

Evaluar la seguridad y la tolerabilidad de Safinamida, 200 mg una vez al día, en comparación con un placebo.

E.2.2

Secondary objectives of the trial

To evaluate the potential efficacy of safinamide 200 mg od, as add-on therapy, on motor function and/or quality of life

Evaluar la posible eficacia de Safinamida 200 mg, una vez al día como tratamiento complementario, en la función motora y/o la calidad de vida.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 30 to 80 years of age inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants who are diagnosed (with MRI confirmation) with possible or probable parkinsonian variant of Multiple System Atrophy less than 2 years ago.
3. Participants with an anticipated survival of at least 3 years in the opinion of the investigator.
Sex
4. Male or female
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies (see Appendix 4):
i. Not a woman of childbearing potential (WOCBP)
OR
ii. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 30 days after the last dose of study intervention.
Informed Consent
5. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Los participantes solo podrán ser incluidos en el estudio si cumplen todos los criterios siguientes:
Edad
1.El participante deberá tener entre 30 y 80 años de edad, ambos inclusive, en el momento de firmar el consentimiento informado.
Tipo de participante y características de la enfermedad
2.Participantes diagnosticados (con confirmación mediante RM) de posible o probable variante parkinsoniana de atrofia multisistémica hace menos de 2 años.
3.Participantes con una supervivencia esperada de al menos 3 años en opinión del investigador.
Sexo
4.Varones o mujeres
• Las mujeres podrán participar si no están embarazadas ni en período de lactancia y se cumple al menos una de las condiciones siguientes (véase el Apéndice 4):
i.No es una mujer en edad fértil (MEF)
O
ii.Es una MEF que se compromete a seguir las normas anticonceptivas durante el período de tratamiento y durante al menos 30 días después de la última dosis de la intervención del estudio.
Consentimiento informado
5.Ser capaz de otorgar el consentimiento informado firmado según se describe en el Apéndice 1, lo que incluye el cumplimiento de los requisitos y restricciones que se enumeran en el documento de consentimiento informado (DCI) y en este protocolo.

E.4

Principal exclusion criteria

Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. History of neurosurgical procedure, including stereotactic surgery.
2. History of Deep Brain Stimulation (DBS)
3. History of bipolar disorder, severe depression, schizophrenia or other psychotic disorder.
4. History of drug and/or alcohol abuse within 12 months prior to screening as defined by the current edition of the Diagnostic and Statistical Manual of Mental Disorders
5. History of dementia (DSM-V criteria)
6. Ophthalmologic history including any of the following conditions: albinism, uveitis, retinitis pigmentosa, retinal degeneration, active retinopathy, severe progressive diabetic retinopathy, inherited retinopathy or family history of hereditary retinal disease.
7. Active hepatitis B or C
8. History of human immunodeficiency virus (HIV) infection
9. Subjects not able to swallow oral medications
10. Subjects with severe orthostatic symptoms
11. Impaired ambulation, i.e. falling more than once per week, bedridden patients or confined to a wheelchair during the whole day.
12. Subjects with active malignant neoplasms.
13. Movement disorders other than MSA (e.g. Parkinson Disease, dementia with Lewy bodies, essential tremor, progressive supranuclear palsy, pharmacological or post-encephalic parkinsonism).
14. Any clinically significant or unstable medical or surgical condition that, in the opinion of the investigator, might preclude safe completion of the study or might affect the results of the study.
Prior/Concomitant Therapy
15. Not on a stable regime, for at least 4 weeks prior to the randomization (baseline visit), of
a. oral levodopa (including controlled release [CR], immediate release [IR] or a combination of CR/IR), with or without benserazide/carbidopa, with or without addition of a catechol O-methyltransferase (COMT) inhibitor
or
b. dopamine agonist, anticholinergic and/or amantadine.
Prior/Concurrent Clinical Study Experience
16. Patients should not have received treatment with monoamine oxidase inhibitors in the 2 weeks prior to the randomization visit, nor treatment with levodopa infusion, pethidine, opiates, opioids, fluoxetine, fluvoxamine in the 4 weeks prior to the randomization visit.
17. Patients should not have received treatment with an oral or depot neuroleptic within 12 weeks prior to the randomization visit.
18. Use of any investigational drug within 30 days prior to screening or 5 half-lives, whichever is the longest.
Diagnostic assessments
19. Montreal Cognitive Assessment (MoCA) ≤ 20
20. Laboratory assessments showing moderate or severe hepatic impairment (2x ULN)
Other Exclusions
21. Allergy/sensitivity or contraindications to the investigational medicinal products (IMPs) or their excipients, anticonvulsants, levodopa or other anti-parkinsonian drugs.
22. Any clinically significant condition which, in the opinion of the Investigator, would not be compatible with study participation or represent a risk for patients while in the study.

Se excluirá del estudio a los participantes que cumplan alguno de los criterios siguientes:
Enfermedades
1.Antecedentes de intervención neuroquirúrgica, incluida la cirugía estereotáctica.
2.Antecedentes de estimulación cerebral profunda (ECP)
3.Antecedentes de trastorno bipolar, depresión grave, esquizofrenia u otro trastorno psicótico.
4.Antecedentes de alcoholismo o toxicomanía en los 12 meses previos a la selección, según se define en la edición vigente del Manual diagnóstico y estadístico de los trastornos mentales
5.Antecedentes de demencia (criterios DSM-V)
6.Antecedentes oftalmológicos, incluidos cualquiera de los siguientes problemas: albinismo, uveítis, retinitis pigmentaria, degeneración retiniana, retinopatía activa, retinopatía diabética progresiva grave, retinopatía hereditaria o antecedentes familiares de retinopatía hereditaria.
7.Hepatitis B o C activa
8.Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH).
9.Sujetos incapaces de tragar medicamentos orales
10.Sujetos con síntomas ortostáticos intensos
11.Deterioro de la deambulación, por ejemplo, caída más de una vez a la semana, postrado en cama o confinado a una silla de ruedas durante todo el día.
12.Sujetos con neoplasias malignas activas.
13.Trastornos del movimiento distintos de la AMS (p. ej., enfermedad de Parkinson, demencia con cuerpos de Lewy, temblor esencial, parálisis supranuclear progresiva, parkinsonismo farmacológico o posencefalítico).
14.Cualquier trastorno médico o quirúrgico clínicamente importante o inestable que, en opinión del investigador, podría impedir la finalización segura del estudio o afectar a los resultados del estudio.
Tratamiento previo/concomitante
15.Sin una pauta estable, durante al menos 4 semanas antes de la aleatorización (visita basal), de
a.levodopa oral (incluidos levodopa de liberación controlada [LC], liberación inmediata [LI] o una combinación de LC/LI), con o sin benserazida/carbidopa, con o sin adición de un inhibidor de la catecol O-metiltransferasa (COMT) o
b.agonista dopaminérgico, anticolinérgico y/o amantadina.
Experiencia previa/concurrente en estudios clínicos
16.Los pacientes no deberán haber recibido tratamiento con inhibidores de la monoaminooxidasa en las 2 semanas previas a la visita de aleatorización, ni tratamiento con infusión de levodopa, ni petidina, opiáceos, fluoxetina, fluvoxamina en las 4 semanas previas a la visita de aleatorización.
17.Los pacientes no podrán haber recibido tratamiento con un neuroléptico oral o de liberación retardada en las 12 semanas previas a la visita de aleatorización.
18.Uso de cualquier fármaco en investigación en los 30 días previos a la selección o 5 semividas, lo que suponga más tiempo.
Evaluaciones diagnósticas
19.Evaluación cognitiva de Montreal (MoCA) < 20
20.Evaluaciones analíticas que indiquen insuficiencia hepática moderada o grave (2 x LSN)
Otras exclusiones
21.Alergia/sensibilidad o contraindicaciones a los medicamentos en investigación (MEI) o sus excipientes, antiepilépticos, levodopa u otros antiparkinsonianos.
22.Cualquier trastorno clínicamente significativo que, en opinión del investigador, no sería compatible con la participación en el estudio o representaría un riesgo para los pacientes durante su participación en el estudio.

E.5 End points

E.5.1

Primary end point(s)

• The nature, frequency, severity, relationship (to study drug), actions taken, and outcome of TEAEs and SAEs.
• Changes in physical and neurological examination findings.
• Changes in vital sign (heart rate, systolic and diastolic blood pressure) values, including occurrence of abnormalities.
• Changes in 12-lead ECG parameter measures, including occurrence of abnormalities.
• Changes in clinical chemistry and hematology values, including shifts from Baseline and occurrence of abnormalities.
• Number of withdrawals (and reason if given).

•Naturaleza, frecuencia, intensidad, relación (con el fármaco del estudio), medidas adoptadas y desenlace de los AAAT y AAG.
•Variaciones en los hallazgos de exploración física y neurológica.
•Variaciones de los valores de las constantes vitales (frecuencia cardíaca, presión arterial sistólica y diastólica), incluida la aparición de anomalías.
•Variaciones de los parámetros del ECG de 12 derivaciones, incluida la aparición de anomalías.
•Variaciones de los valores de bioquímica clínica y hematología, incluidas las desviaciones con respecto a los valores basales y la aparición de anomalías.
•Número de retiradas (y motivo si se indica).

E.5.1.1

Timepoint(s) of evaluation of this end point

Outcome will be assessed after 12 weeks of treatment, when progression is unlikely to be a confounder of change.

El resultado se evaluará después de 12 semanas de tratamiento, cuando es improbable que la progresión sea un factor de confusión.

E.5.2

Secondary end point(s)

• The change from baseline to week 12 in the goniometric measurement for “lateral” displacement
• Change from baseline at week 12 in Unified MSA Rating Scale, MSA Health-Related Quality of Life (MSA-QoL) scale, Montreal Cognitive Assessment (MoCA) scale, Unified Dystonia Rating Scale (UDRS).

•Variación entre la visita basal y la semana 12 de la medida goniométrica del desplazamiento lateral.
•Variación entre la visita basal y la semana 12 en la Escala unificada de valoración de la AMS, la Escala de calidad de vida relacionada con la salud en la AMS (MSA-QoL), la Escala de evaluación cognitiva de Montreal (MoCA) y la Escala unificada de valoración de la distonía (UDRS).

E.5.2.1

Timepoint(s) of evaluation of this end point

Outcome will be assessed after 12 weeks of treatment, when progression is unlikely to be a confounder of change.

El resultado se evaluará después de 12 semanas de tratamiento, cuando es improbable que la progresión sea un factor de confusión.

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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 vistia del ultimo paciente

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

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)

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

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)

standard of care

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

2019-07-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-01-05

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