Clinical Trials Register

Summary
EudraCT Number:	2018-004484-31
Sponsor's Protocol Code Number:	NN9931-4492
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:	2019-05-24
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

2018-004484-31

A.3

Full title of the trial

Investigation of efficacy and safety of semaglutide s.c. once-weekly versus placebo in subjects with non-alcoholic steatohepatitis and compensated liver cirrhosis

Investigación sobre la eficacia y la seguridad de semaglutida s.c. administrada una vez a la semana frente a placebo en sujetos con esteatohepatitis no alcohólica y cirrosis hepática compensada

A.3.1

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

A research study on how semaglutide works in people with fatty liver disease and liver damage

Estudio de investigación sobre el mecanismo de acción de semaglutida en personas con enfermedad de hígado graso y daño hepático

A.4.1

Sponsor's protocol code number

NN9931-4492

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1224-4062

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	Novo Nordisk A/S
B.1.3.4	Country	Denmark
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	Novo Nordisk A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novo Nordisk A/S
B.5.2	Functional name of contact point	Clinical Disclosure (1452)
B.5.3	Address:
B.5.3.1	Street Address	Novo Allé
B.5.3.2	Town/ city	Bagsvaerd
B.5.3.3	Post code	2880
B.5.3.4	Country	Denmark
B.5.6	E-mail	clinicaltrials@novonordisk.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	Ozempic®
D.2.1.1.2	Name of the Marketing Authorisation holder	Novo Nordisk A/S
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.3.1	Product name	Semaglutide B 3.0 mg/ml PDS290
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	semaglutide
D.3.9.1	CAS number	910463-68-2
D.3.9.3	Other descriptive name	SEMAGLUTIDE
D.3.9.4	EV Substance Code	SUB32188
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	1.34
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	Yes
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	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Non-alcoholic steatohepatitis
Compensated liver cirrhosis

Esteatohepatitis no alcohólica
Cirrosis de hígado compensada

E.1.1.1

Medical condition in easily understood language

Non-alcoholic steatohepatitis (NASH)
Compensated liver cirrhosis

Esteatohepatitis no alcohólica (EHNA)
Cirrosis de hígado compensada

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10053219
E.1.2	Term	Non-alcoholic steatohepatitis
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10024667
E.1.2	Term	Liver cirrhosis
E.1.2	System Organ Class	10019805 - Hepatobiliary 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 investigate the effect of semaglutide subcutaneous (s.c.) 2.4 mg once-weekly on liver fibrosis compared with placebo in subjects with NASH and compensated fibrosis stage 4

Investigar el efecto de semaglutida s.c. 2,4 mg una vez a la semana sobre la EHNA en comparación con un placebo en sujetos con EHNA y fibrosis en estadio 4 compensada.

E.2.2

Secondary objectives of the trial

1. To investigate the effect of semaglutide s.c. 2.4 mg once-weekly on NASH compared with placebo in subjects with NASH and compensated fibrosis stage 4
2, To evaluate the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly compared with placebo in subjects with NASH and compensated fibrosis stage 4

1. Investigar el efecto de semaglutida s.c. 2,4 mg una vez a la semana sobre la EHNA en comparación con un placebo en sujetos con EHNA y fibrosis en estadio 4 compensada
2. Evaluar la seguridad y la tolerabilidad de semaglutida s.c. 2,4 mg una vez a la semana en comparación con un placebo en sujetos con EHNA y fibrosis en estadio 4 compensada

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent.
- Histologic evidence of NASH and fibrosis stage 4 according to the NASH CRN classification based on central pathologist evaluation of a liver biopsy obtained within 360 days prior to screening. In subjects who have never had a liver biopsy showing NASH and F4, liver stiffness above14 kPa by FibroScan® at screening must be documented before subjects can have a trial-related liver biopsy
- A histological NAFLD activity score (NAS) equal to or above 3 with a score of 1 or more in lobular inflammation and hepatocyte ballooning based on central pathologist evaluation
- Body mass index equal to or above 27 kg/m^2

Los sujetos son elegibles para ser incluidos en el ensayo solo si se aplican todos los criterios siguientes:
a. Consentimiento informado obtenido antes de cualquier actividad relacionada con el ensayo. Las actividades relacionadas con el ensayo son cualquier procedimiento que se lleve a cabo como parte del ensayo, incluidas las actividades para determinar la idoneidad del ensayo.
b. Hombre o mujer, de 18 a 75 años (ambos inclusive) en el momento de firmar el consentimiento informado.
c. Evidencia histológica de EHNA y fibrosis en estadio 4, según la clasificación EHNA CRN, basada en la evaluación de una biopsia de hígado del patólogo principal obtenida dentro de los 360 días anteriores a la selección. En sujetos que nunca se les haya hecho una biopsia de hígado que muestre EHNA y F4, se debe documentar una rigidez hepática> 14 kPa por medio de FibroScan® en la selección, antes de que a los sujetos se les pueda realizar una biopsia de hígado relacionada con el ensayo.
d. Un valor histológico de actividad NAFLD (NAS) ≥ 3 con un valor de 1 o más en inflamación lobular y balonamiento de hepatocitos según la evaluación del patólogo principal.
e. Índice de masa corporal ≥27 kg/m2

E.4

Principal exclusion criteria

- Presence or history of hepatic decompensation (e.g. ascites, variceal bleeding, hepatic encephalopathy or spontaneous bacterial peritonitis) or liver transplantation
- Presence or history of gastroesophageal varices within the past 360 days prior to screening. For subjects with no known history of gastroesophageal varices and with a Fibroscan® equal to or above 20 kPa and thrombocytes equal to or below 150,000, a esophagogastroduodenoscopy must be performed to evaluate presence of gastroesophageal varices
- Presence or history of hepatocellular carcinoma
- Treatment with vitamin E (at doses equal to or above 800 IU/day) or pioglitazone which has not been at a stable dose in the opinion of the investigator in the period from 90 days prior to screening
- Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the period from 90 days prior to screening
- Treatment with other glucose lowering agent(s) (apart from what is listed in the exclusion criterion above) or weight loss medication not stable in the opinion of the investigator in the period from 28 days prior to screening

• Presencia o antecedentes de descompensación hepática (por ejemplo, ascitis, varices hemorrágicas, encefalopatía hepática o peritonitis bacteriana espontánea) o trasplante de hígado.
• Presencia o antecedentes de varices gastroesofágicas en los 360 días previos a la selección. En los sujetos sin antecedentes conocidos de varices gastroesofágicas y con un Fibroscan® ≥ 20 kPa y un recuento de plaquetas ≤ 150.00016 deberá realizarse una esofagogastroduodenoscopia para evaluar la presencia de varices gastroesofágicas
• Presencia o antecedentes de carcinoma hepatocelular.
• Tratamiento con vitamina E (en dosis ≥ 800 UI/día) o pioglitazona que, en opinión del investigador, no se ha mantenido en una dosis estable en el período correspondiente a los 90 días previos a la selección.
• Tratamiento con agonistas del receptor del péptido glucagonoide-1 (AR GLP-1) en el período correspondiente a los 90 días previos a la selección.
• Tratamiento con otros hipoglucemiantes (aparte de los citados en el criterio de exclusión anterior) o medicamentos para adelgazar que, en opinión del investigador, no se ha mantenido en una dosis estable en el período correspondiente a los 28 días previos a la selección.

E.5 End points

E.5.1

Primary end point(s)

Relative change in liver stiffness measured by MRE

Variacion relativa en la rigidez hepática medida mediante ERM

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline (week 0) to visit 12 (week 48)

Desde el momento basal (semana 0) hasta la visita 12 (semana 48)

E.5.2

Secondary end point(s)

1. Relative change in liver fat content (%) measured by MRI-PDFF
2. At least one stage of liver fibrosis improvement with no worsening of NASH (yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation, hepatocyte ballooning or steatosis according to the NASH CRN criteria)
3. NASH resolution (yes/no) (defined by the NASH CRN as lobular inflammation 0 – 1 and ballooning 0)
4. Change in Stage of fibrosis according to the NASH CRN fibrosis score
5. Change in NAFLD activity score (NAS) according to the NASH CRN criteria
6. Number of treatment emergent adverse events

1. Variación relativa del contenido de grasa hepática (%) medido mediante RM-PDFF
2. Mejoría de la fibrosis hepática en al menos un estadio, sin empeoramiento de la EHNA (sí/no) (empeoramiento definido como un aumento de al menos un estadio de la inflamación lobulillar, balonización de los hepatocitos o esteatosis conforme a los criterios CRN sobre la EHNA)
3. Resolución de la EHNA (sí/no) (definida por los criterios CRN sobre la EHNA como inflamación lobulillar de 0-1 y balonización de 0)
4. Variación del estadio de fibrosis según la puntuación de fibrosis de los criterios CRN sobre la EHNA
5. Variación de la puntuación de actividad de la esteatosis hepática no alcohólica (NAS) según los criterios CRN sobre la EHNA
6. Número de acontecimientos adversos aparecidos durante el tratamiento

E.5.2.1

Timepoint(s) of evaluation of this end point

All secondary endpoints:
From baseline (week 0) to visit 12 (week 48)

Todos los criterios de valoración secundarios:
desde el momento basal (semana 0) hasta la visita 12 (semana 48)

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tolerabilidad

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

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

European Union

United States

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

UVUP

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:

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)

None

Ninguno

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

2019-05-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-22

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

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