Clinical Trials Register

Summary
EudraCT Number:	2019-002076-13
Sponsor's Protocol Code Number:	NS-065/NCNP-01-301
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:	2021-01-05
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

2019-002076-13

A.3

Full title of the trial

A Phase 3 Randomized, Double-blind, Placebo-controlled, Multi-center Study to Assess the Efficacy and Safety of Viltolarsen in Ambulant Boys with Duchenne Muscular Dystrophy (DMD)

Studio multicentrico di fase 3 randomizzato, in doppio cieco, controllato con placebo per valutare l’efficacia e la sicurezza di viltolarsen in ragazzi deambulanti con distrofia muscolare di Duchenne (DMD)

A.3.1

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

This is a randomized, double-blind, Placebo-controlled sudy to evaluate the Efficacy and Safety of Viltolarsen in Ambulant Boys with Duchenne Muscular Dystrophy (DMD)

Questo è uno studio randomizzato, in doppio cieco, controllato con placebo, per valutare l'efficacia e la sicurezza di Viltolarsen in ragazzi deambulanti con distrofia muscolare di Duchenne (DMD)

A.3.2

Name or abbreviated title of the trial where available

RACER-53

A.4.1

Sponsor's protocol code number

NS-065/NCNP-01-301

A.5.4

Other Identifiers

Name:

US IND

Number:

127474

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	NS Pharma, 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	NS Pharma, Inc.
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Nippon Shinyaku Co., Ltd
B.4.2	Country	Japan
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medpace
B.5.2	Functional name of contact point	Wendy Van den Branden
B.5.3	Address:
B.5.3.1	Street Address	Technologielaan 11
B.5.3.2	Town/ city	Leuven
B.5.3.3	Post code	B-3001
B.5.3.4	Country	Belgium
B.5.4	Telephone number	0032163918702703
B.5.5	Fax number	003278480351
B.5.6	E-mail	regsubmissions@medpace.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	No
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	Viltolarsen
D.3.2	Product code	[NS-065/NCNP-01]
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VILTOLARSEN
D.3.9.1	CAS number	2055732-84-6
D.3.9.2	Current sponsor code	NS-065/NCNP-01
D.3.9.4	EV Substance Code	SUB195543
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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 infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Duchenne Muscular Dystrophy (DMD)

Distrofia Muscolare di Duchenne

E.1.1.1

Medical condition in easily understood language

Muscular Dystrophy

Distrofia Muscolare

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

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	10013801
E.1.2	Term	Duchenne muscular dystrophy
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic 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 compare the efficacy of viltolarsen administered intravenously at weekly doses of 80 mg/kg over a 48-week treatment period vs. placebo controls in ambulant boys ages 4 to <8 years with DMD using Time to Stand Test (TTSTAND) as a measure of strength and function.

Confrontare l’efficacia di viltolarsen somministrato per via endovenosa in dosi settimanali da 80 mg/kg nell’arco di un periodo di trattamento di 48 settimane rispetto a controlli con placebo in ragazzi deambulanti di età compresa tra 4 e <8 anni affetti da DMD mediante test del tempo impiegato per alzarsi in piedi (Time to Stand Test, TTSTAND) come misura di forza e funzionalità.

E.2.2

Secondary objectives of the trial

-To compare the efficacy of viltolarsen administered intravenously at weekly doses of 80 mg/kg in ambulant boys ages 4 to <8 years with DMD over a 48-week treatment period vs. placebo controls using hierarchical strength and endurance outcomes
-To evaluate the safety and tolerability of viltolarsen administered intravenously at weekly doses of 80 mg/kg in ambulant boys ages 4 to <8 years with DMD

-Confrontare l’efficacia di viltolarsen somministrato per via endovenosa in dosi settimanali da 80 mg/kg in ragazzi deambulanti di età compresa tra 4 e <8 anni affetti da DMD nell’arco di un periodo di trattamento di 48 settimane rispetto a controlli con placebo usando esiti gerarchici di forza e resistenza
-Valutare la sicurezza e la tollerabilità di viltolarsen somministrato per via endovenosa in dosi settimanali da 80 mg/kg in ragazzi deambulanti di età compresa tra 4 e < 8 anni affetti da DMD;

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1-Participant’s parent(s) or legal guardian(s) has (have) provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization, where applicable, prior to any study-related procedures; participants will be asked to give written or verbal assent according to local requirements;
2. Participant has a confirmed diagnosis of DMD defined as:
a. Participant is male with clinical signs compatible with DMD; and
b. Participant has a confirmed DMD mutation(s) in the dystrophin gene that is amenable to skipping of exon 53 to restore the dystrophin mRNA reading frame including determination of unambiguously defined exon boundaries (using techniques such as multiplex ligation-dependent probe amplification [MLPA], comparative genomic hybridization [CGH] array or other techniques with similar capability);
3. Participant is = 4 years and <8 years of age at time of first infusion in the study;
4. Participant is able to walk independently without assistive devices;
5. Participant is able to complete the TTSTAND without assistance in <10 seconds, as assessed at the Screening Visit;
6. Participant and parent(s)/guardian(s) are willing and able to comply with scheduled visits, study drug administration plan, and study procedures;
7. Participant must be on a stable dose of glucocorticoid (GC) for at least 3 months prior to first dose of study drug and is expected to remain on stable

1. I genitori o tutori legali del partecipante hanno fornito il consenso informato scritto e l’autorizzazione della Legge sulla portabilità e responsabilità delle polizze di assicurazione sanitaria (Health Insurance Portability and Accountability Act, HIPAA), ove applicabile, prima di iniziare qualsiasi procedura correlata allo studio; ai partecipanti sarà chiesto di dare il proprio assenso scritto o verbale secondo i requisiti locali;
2. Il partecipante presenta una diagnosi confermata di DMD definita come:
a. Il partecipante è di sesso maschile con segni clinici compatibili con la DMD; e
b. Il partecipante presenta una o più mutazioni della DMD confermate a livello del gene della distrofina, trattabili con skipping dell’esone 53 volto a ripristinare il frame di lettura dell’RNA messaggero (messenger RNA, mRNA) della distrofina, inclusa la determinazione dei confini dell’esone definiti in modo univoco (usando tecniche quali amplificazione legatura-dipendente multipla della sonda (multiplex ligation-dependent probe amplification, MLPA), matrice di ibridazione genomica comparativa (comparative genomic hybridization, CGH) o altre tecniche con capacità simile);
3. Il partecipante ha un’età compresa tra =4 e <8 anni al momento della prima infusione nello studio;
4. Il partecipante è in grado di camminare da solo senza dispositivi di assistenza;
5. Il partecipante è in grado di completare il TTSTAND senza assistenza in <10 secondi, secondo la valutazione della visita di screening;
6. Il partecipante e i genitori o tutori legali sono disposti a, e in grado di, attenersi alle visite programmate, al piano di somministrazione del farmaco dello studio e alle procedure dello studio;
7. Il partecipante deve assumere una dose stabile di glucocorticoide (GC) per almeno i 3 mesi precedenti alla prima dose del farmaco in studio e deve continuare a farlo per tutta la durata dello studio.

E.4

Principal exclusion criteria

1. Participant has current or history of chronic systemic fungal or viral infections;
2. Participant has had an acute illness within 4 weeks prior to the first dose of study drug based on the Principal Investigator's judgment/discretion;
3. Participant has evidence of symptomatic cardiomyopathy (Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary);
4. Participant has an allergy or hypersensitivity to the study drug or to any of its constituents;
5. Participant has severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the investigator;
6. Participant has previous or ongoing medical condition, medical history, physical findings or laboratory abnormalities that could affect safety, make it unlikely that treatment and follow-up will be correctly completed or impair the assessment of study results, in the opinion of the investigator;
7. Participant has had surgery within the 3 months prior to the first anticipated administration of study drug or surgery is planned for anytime during the duration of the study;
8. Participant has positive test results for hepatitis B antigen, hepatitis C antibody or human immunodeficiency virus (HIV) antibody at screening;
9. Participant is currently taking any other investigational drug or has taken any other investigational drug within 3 months prior to the first dose of study drug or within 5 times the halflife of a medication, whichever is longer;
10. Participant was previously enrolled in an interventional study of viltolarsen.
11. Participant is currently taking any other exon skipping agent or has taken any other exon skipping agent within 3 months prior to the first dose of study drug.
12. Participant has taken any gene therapy.
13.Participant has inadequate renal function, as defined by serum Cystatin C greater than 1.5 × upper limit of normal (ULN) at the Screening Visit. If the value is greater than 1.5 × ULN, the serum Cystatin C will be repeated once; if the repeated test result is still greater than 1.5 × ULN, the participant should be excluded

1. Il partecipante presenta attualmente, o in anamnesi, infezioni micotiche o virali sistemiche croniche;
2. Il partecipante ha avuto una malattia acuta nelle 4 settimane precedenti la prima dose di farmaco dello studio, in base al giudizio/a discrezione dello Sperimentatore principale;
3. Il partecipante presenta evidenza di cardiomiopatia sintomatica (NB: un’anomalia cardiaca asintomatica in fase di analisi non comporterebbe l’esclusione);
4. Il partecipante presenta allergia o ipersensibilità al farmaco dello studio o a qualsiasi suo componente;
5. Il partecipante presenta problemi comportamentali o cognitivi seri che, a parere dello sperimentatore, precludono la partecipazione allo studio;
6. Il partecipante presenta una condizione medica precedente o attuale, un’anamnesi medica, risultati fisici o anomalie di laboratorio che potrebbero compromettere la sicurezza, rendere improbabile che il trattamento e il follow-up siano completati correttamente o compromettere la valutazione dei risultati dello studio, a parere dello sperimentatore;
7. Il partecipante ha subito un’intervento chirurgico nei 3 mesi precedenti la prima somministrazione prevista del farmaco dello studio oppure si pianifica un intervento chirurgico in qualsiasi momento nel corso dello studio;
8. Il partecipante presenta risultati positivi al test per gli antigeni dell’epatite B, degli anticorpi dell’epatite C o del virus dell’immunodeficienza umana (human immunodeficiency virus, HIV) allo screening;
9. Il partecipante sta attualmente assumendo un altro farmaco sperimentale o ne ha assunto uno nei 3 mesi precedenti la prima dose di farmaco dello studio o in 5 volte il tempo di emivita di un farmaco, a seconda di quale sia il periodo più lungo;
10. Il partecipante è stato precedentemente arruolato in uno studio interventistico di viltolarsen;
11. Il partecipante sta attualmente assumendo un altro agente per lo skipping dell’esone o ne ha assunto uno nei 3 mesi precedenti la prima dose di farmaco dello studio;
12. Il partecipante ha assunto una terapia genica.
13.Il partecipante ha una funzione renale inadeguata, come definita dai livelli di cistatina C sierica 1,5 volte maggiori rispetto al limite superiore della normalità (Upper Limit of Normal, ULN) alla Visita di screening. Se il valore è 1,5 volte maggiore rispetto all’ULN, il test della cistatina C sierica sarà ripetuto una volta; se il risultato del test ripetuto è ancora 1,5 volte maggiore rispetto all’ULN, il partecipante deve essere escluso

E.5 End points

E.5.1

Primary end point(s)

TTSTAND

E.5.1.1

Timepoint(s) of evaluation of this end point

At 48 weeks treatment

A 48 settimane di trattamento

E.5.2

Secondary end point(s)

- Hierarchical analyses of the following strength and endurance measures:
- Time to Run/Walk 10 Meters Test (TTRW)
- Six-minute Walk Test (6MWT)
- North Star Ambulatory Assessment (NSAA)
- Time to Climb 4 Steps Test (TTCLIMB)
- Hand-held dynamometer (elbow extension, elbow flexion, knee extension and knee flexion on the dominant side only)

- Analisi gerarchica a 48 settimane di trattamento delle seguenti misure di forza e resistenza:
- Time to Run/Walk 10 Meters Test (TTRW)
- Six-minute Walk Test (6MWT)
- North Star Ambulatory Assessment (NSAA)
- Time to Climb 4 Steps Test (TTCLIMB)
- Forza muscolare quantitativa misurata mediante dinamometro palmare (estensione e flessione del gomito, estensione e flessione del ginocchio solo sul lato dominante)

E.5.2.1

Timepoint(s) of evaluation of this end point

At 48 weeks treatment (first 5 bullets)
At each study visit (last 10 bullets)

A 48 settimane di trattamento (primi 5 punti)
Ad ogni visita di studio (ultimi 10 punti)

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

Australia

Brazil

Canada

Chile

Japan

Korea, Republic of

Russian Federation

Taiwan

Turkey

United States

Belgium

France

Italy

Netherlands

Poland

Spain

United Kingdom

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

The end of study date is defined as the date when the last participant at the site is assessed or receives an intervention for evaluation in the study (i.e., last participant last visit).

La data di fine studio è definita come la data in cui l'ultimo partecipante al centro viene valutato o riceve un intervento per la valutazione nello studio (ovvero ultima visita dell'ultimo partecipante).

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

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

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

Assent only to be provided, where appropriate, due to patient age

A causa dell'età del paziente sarà richiesto il solo assenso

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)

At the completion of the study, an open-label extension study may be available to patients (who successfully complete the double-blind study) in countries where Viltolarsen is not commercially available.

Al completamento dello studio, potrebbe essere disponibile uno studio di estensione in aperto per i pazienti (che completano con successo lo studio in doppio cieco) in paesi in cui Viltolarsen non è disponibile in commercio.

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

2020-01-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-10

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

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