ICH GCP - EU Clinical trials Registry - 2021-005478-24 (ES)

Summary
EudraCT Number:	2021-005478-24
Sponsor's Protocol Code Number:	DYNE251-DMD-201
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-10-07
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

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Dyne Therapeutics, 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	Dyne Therapeutics, 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	Dyne Therapeutics, Inc
B.5.2	Functional name of contact point	Dyne Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	1560 Trapelo Rd
B.5.3.2	Town/ city	Waltham, MA
B.5.3.3	Post code	02451
B.5.3.4	Country	United States
B.5.4	Telephone number	-+34900834223
B.5.6	E-mail	RegistroEspanolDeEstudiosClinicos@druginfo.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	DYNE-251
D.3.2	Product code	DYNE-251
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
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	NA
D.3.9.1	CAS number	2725863-42-1
D.3.9.2	Current sponsor code	DYNE-251
D.3.9.3	Other descriptive name	Fragment antibody targeting human TfR1 conjugated to phosphorodiamidate morpholino oligomer
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	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	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

Distrofia muscular de Duchenne

E.1.1.1

Medical condition in easily understood language

Muscular disease causing progressive loss of skeletal, pulmonary, cardiac and muscle function

Enfermedad muscular que causa pérdida progresiva de la función del músculo esquelético, pulmonar, cardíaco y liso.

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 evaluate the safety and tolerability of multiple IV doses of DYNE-251 administered to participants with DMD

To evaluate dystrophin protein levels in muscle tissue following multiple IV doses of DYNE-251 administered to participants with DMD

Evaluar la seguridad y la tolerabilidad de dosis IV múltiples de DYNE-251 administradas a pacientes con DMD.

Evaluar las concentraciones de proteína distrofina en el tejido muscular después de administrar varias dosis IV de DYNE-251 a pacientes con DMD.

E.2.2

Secondary objectives of the trial

To evaluate the effects on muscle tissue exon skipping, percent dystrophin-positive fibers (PDPFs), and plasma creatine kinase (CK) following multiple IV doses of DYNE-251 administered to participants with DMD

To evaluate muscle function following multiple IV doses of DYNE-251 administered to participants with DMD

To evaluate plasma and muscle tissue PK following multiple IV doses of DYNE-251 administered to participants with DMD

To evaluate the immunogenicity of multiple IV doses of DYNE-251 administered to participants with DMD

Evaluar los efectos sobre la omisión de exones en el tejido muscular, el porcentaje de fibras positivas para la distrofina (PDPF, percent dystrophin-positive fibers) y la creatina cinasa (CK) plasmática tras la administración de dosis IV múltiples de DYNE-251 a pacientes con DMD.

Evaluar la función muscular tras la administración de dosis IV múltiples de DYNE-251 a pacientes con DMD.

Evaluar la farmacocinética en plasma y tejido muscular tras la administración de dosis IV múltiples de DYNE 251 a pacientes con DMD.

Evaluar la inmunogenicidad de dosis IV múltiples de DYNE-251 administradas a pacientes con DMD

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age 4 to 16 years inclusive, at the time of informed consent/assent.
• Male with a confirmed DMD mutation in the dystrophin gene characterized by exon deletion amenable to exon 51 skipping.
• Upper extremity muscle group that is amenable to muscle biopsy.
• Brooke Upper Extremity Scale score of 1 or 2.
• Ambulatory or non-ambulatory. A non-ambulatory participant must have been non-ambulatory for <2 years before enrolment.
• Receiving a stable dosage of glucocorticoids for at least 12 weeks prior to the start of study drug administration.
• Left ventricular ejection fraction of ≥50% by echocardiogram or ≥55% by cardiac magnetic resonance imaging (MRI).

• De 4 a 16 años inclusive, en el momento del consentimiento/asentimiento informado.
• Varón con una mutación DMD confirmada en el gen de la distrofina caracterizada por la eliminación del exón susceptible de omisión del exón 51.
• Grupo muscular de la extremidad superior que es susceptible de biopsia muscular.
• Puntuación de 1 o 2 en la escala de extremidades superiores de Brooke.
• Ambulatorio o no ambulatorio. Un participante no ambulatorio debe haber sido no ambulatorio durante <2 años antes de la participacion.
• Recibir una dosis estable de glucocorticoides durante al menos 12 semanas antes del inicio de la administración del fármaco del estudio.
• Fracción de eyección del ventrículo izquierdo ≥50 % por ecocardiograma o ≥55 % por resonancia magnética (RM) cardíaca.

E.4

Principal exclusion criteria

• Uncontrolled clinical symptoms and signs of congestive heart failure (CHF).
• Any change in prophylaxis/treatment for CHF within 3 months prior to the start of study treatment.
• History of major surgical procedure within 12 weeks prior to the start of study drug administration or an expectation of a major surgical procedure during the study.
• Requirement of daytime ventilator assistance.
• Percent predicted FVC <40 % (applies only for participants who are age ≥7 years).
• Receipt of eteplirsen, or alternative exon-skipping/dystrophin-modifying therapy, within 12 weeks of randomization.
• Receipt of non-exon skipping investigational drug within 4 months before the start of study drug administration.
• Receipt of gene therapy at any time.

• Síntomas y signos clínicos no controlados de insuficiencia cardíaca congestiva (ICC).
• Cualquier cambio en la profilaxis/tratamiento para CHF dentro de los 3 meses anteriores al inicio del tratamiento del estudio.
• Historial de procedimiento quirúrgico mayor dentro de las 12 semanas anteriores al inicio de la administración del fármaco del estudio o expectativa de un procedimiento quirúrgico mayor durante el estudio.
• Requerimiento de respiración asistida diurna.
• Porcentaje previsto de CVF <40 % (se aplica solo a participantes de ≥7 años de edad).
• Recibir eteplirsen, o terapia alternativa de omisión de exón/modificadora de distrofina, dentro de las 12 semanas posteriores a la aleatorización
• Recibir del fármaco en investigación sin omisión de exón en los 4 meses anteriores al inicio de la administración del fármaco del estudio
• Recibir terapia génica en cualquier momento.

E.5 End points

E.5.1

Primary end point(s)

1. Number and proportion of participants with treatment-emergent adverse events (TEAEs), treatment emergent serious adverse events (TESAEs), TEAEs considered related to study drug, and TEAEs leading to discontinuation from study drug and discontinuation from the study.
2. Change from Baseline in dystrophin protein levels in muscle tissue as determined by Western blot analysis at Week 25

1. Número y proporción de pacientes con acontecimientos adversos aparecidos durante el tratamiento (AAAT), acontecimientos adversos graves aparecidos durante el tratamiento (AAGAT), AAAT que se consideren relacionados con el fármaco del estudio y AAAT que motiven la suspensión del fármaco del estudio y la retirada del estudio.
2. Variación de la concentración de proteína distrofina en el tejido muscular, determinada mediante inmunotransferencia, entre el momento basal y la semana 25.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. All visits from screening to end of study
2. Screening and week 25 visit

1. Todas las visitas desde la selección hasta el final del estudio
2. Selección y visita de la semana 25

E.5.2

Secondary end point(s)

1. Change from Baseline in muscle tissue exon 51 skipping levels at Week 25
2. Change from Baseline in muscle tissue PDPF at Week 25
3. Change from Baseline in plasma CK levels up to Week 145
4. Change from Baseline in North Star Ambulatory Assessment (NSAA) total score in ambulatory participants up to Week 145
5. Change from Baseline in time to rise from floor in ambulatory participants up to Week 145
6. Change from Baseline in 10-meter run/walk (10-MRW) time in ambulatory participants up to Week 145
7. Change from Baseline in performance upper limb (PUL) scale Version 2.0 score up to Week 145
8. Change from Baseline in percent predicted forced vital capacity (FVC) up to Week 145
9. Maximum observed drug concentration (Cmax)
10. Time to maximum concentration (tmax)
11. Area under the concentration-time curve (AUC) from hour 0 to the last measurable concentration (AUCtlast)
12. AUC extrapolated to infinity (AUC∞)
13. Apparent terminal elimination rate constant (λZ)
14. Apparent terminal elimination half-life (t½)
15. Plasma clearance (CL)
16. Volume of distribution at the terminal phase (Vz), if appropriate
17. Volume of distribution at steady state (Vss), if appropriate
18. Tissue phosphorodiamidate morpholino oligomer (PMO) concentration
19. Incidence of antidrug antibodies (ADAs)

1. Variación de los niveles de omisión del exón 51 en tejido muscular entre el momento basal y la semana 25.
2. Variación de la puntuación PDPF entre el momento basal y la semana 25.
3. Variación de la concentración plasmática de CK entre el momento basal y la semana 145.
4. Variación de la puntuación total de la evaluación ambulatoria North Star (NSAA) entre el momento basal y la semana 145.
5. Variación con respecto al momento basal del tiempo en levantarse del suelo en los pacientes ambulatorios hasta la semana 145.
6. Variación con respecto al momento basal del tiempo en correr/caminar 10 metros (10 MRW) en los pacientes ambulatorios hasta la semana 145.
7. Variación de la puntuación en la escala funcional de las extremidades superiores (PUL), versión 2.0, entre el momento basal y la semana 145.
8. Variación del porcentaje de la capacidad vital forzada (FVC) teórica entre el momento basal y la semana 145.
9. Concentración máxima observada (Cmáx) del fármaco.
10. Tiempo hasta la concentración máxima (tmáx).
11. Área bajo la curva (AUC) de la concentración frente al tiempo desde el momento 0 hasta la última concentración medible (AUCúlt).
12. AUC extrapolada al infinito (AUC∞).
13. Constante de velocidad de eliminación terminal aparente (λZ).
14. Semivida de eliminación terminal aparente (t½).
15. Aclaramiento plasmático (CL).
16. Volumen de distribución en la fase terminal (Vz), si procede.
17. Volumen de distribución en estado de equilibrio estacionario (Vee).
18. Concentración de oligómero morfolino fosforodiamidato (PMO) tisular.
19. Incidencia de anticuerpos contra el fármaco (ACF).

E.5.2.1

Timepoint(s) of evaluation of this end point

- For endpoints 1 and 2: Screening and week 25 visit
- For endpoint 3: Screening, D1/pre-dose, D3, D8, W5, W9, W13, W17, W21, W25, W37, W29, W33, W41, W45, W49, W53, W57, W65, W69, W77, W81, W89, W93, W101, W105, W113, W117, W125, W129, W137, W141, W61, W85, W109, W133, W73, W121, W97, W145
- For endpoints 4 through 8: Screening, W13, W25, W37, W49, W73, W121, W97, W145
- For endpoints 9 through 17: D1/Pre-dose, D1/EOI, D1/15min-post, D1/1h-post, D1/4h-post, D1/8h-post, D1/12h-post, D2, D3, D8, W5, W25, W49, W97, W145
- For endpoint 18: Screening and week 25
- For endpoint 19: Screening, W5, W9, W13, W17, W21, W25, W37, W29, W33, W41, W45, W49, W53, W57, W65, W69, W77, W81, W89, W93, W101, W105, W113, W117, W125, W129, W137, W141, W61, W85, W109, W133, W73, W121, W97, W145

- Para los criterios de valoración (CdV) 1 y 2: Selección y S25
- CdV 3: Selección, D1/dosis previa, Día (D) 3, D8, Semana (S) 5, S9, S13, S17, S21, S25, S37, S29, S33, S41, S45, S49, S53, S57, S65, S69, S77, S81, S89, S93, S101, S105, S113, S117, S125, S129, S137, S141, S61, S85, S109, S133, S73, S121, S97, S145
- CdV de 4 a 8: Selección , S13, S25, S37, S49, S73, S121, S97, S145
- CdV de 9 a 17: D1/Dosis previa, D1/FDI, D1/15min-despues, D1/1h-despues, D1/4h-despues, D1/8h-despues, D1/12h-despues, D2, D3, D8, S5, S25, S49, S97, S145
- CdV 18: Selección y S25
- CdV 19: S5, S9, S13, S17, S21,S25, S37, S29, S33, S41, S45, S49, S53, S57, S65, S69, S77,S81, S89, S93, S101, S105, S113, S117, S125, S129, S137, s141, S61, S85, S109, S133, S73, S121, S97, S145

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.1.1

First administration to humans

Yes

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

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

Canada

United States

France

Spain

Germany

Italy

Belgium

Ireland

United Kingdom

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 visita del último 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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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