Clinical Trials Register

Summary
EudraCT Number:	2022-001629-65
Sponsor's Protocol Code Number:	D7830C00004
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:	2023-01-04
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

2022-001629-65

A.3

Full title of the trial

A Randomised, Double-blind, Placebo-Controlled, Multi-Center Phase 2b Study to Evaluate the Efficacy, Safety and Tolerability of AZD2693 in Participants with Non-Cirrhotic Non-Alcoholic Steatohepatitis (NASH) with Fibrosis Who Are Carriers of the PNPLA3 rs738409 148M Risk Allele

Studio di fase IIb randomizzato, multicentrico, in doppio cieco, controllato con placebo volto a valutare l’efficacia, la sicurezza e la tollerabilità di AZD2693 in pazienti affetti da steatoepatite non alcolica non cirrotica (NASH) con fibrosi e portatori dell’allele di rischio di PNPLA3 rs738409 148M

A.3.1

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

A Study to Evaluate the Efficacy, Safety and Tolerability of AZD2693 given by subcutaneous injection in adult participants with non-cirrhotic nonalcoholic steatohepatitis with fibrosis and who have the PNPLA3 rs738409 148M Genetic Marker

Studio per valutare l’efficacia, la sicurezza e la tollerabilità di AZD2693 somministrato come iniezione sottocutanea in pazienti adulti affetti da steatoepatite non alcolica non cirrotica (NASH) con fibrosi e portatori dell’allele di rischio di PNPLA3 rs738409 148M

A.3.2

Name or abbreviated title of the trial where available

FORTUNA

A.4.1

Sponsor's protocol code number

D7830C00004

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	ASTRAZENECA AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Astrazeneca
B.5.2	Functional name of contact point	Clinical Study Information Center
B.5.3	Address:
B.5.3.1	Street Address	1800 Concorde Pike
B.5.3.2	Town/ city	Wilmington
B.5.3.3	Post code	DE 19803
B.5.3.4	Country	United States
B.5.4	Telephone number	+18772409479
B.5.6	E-mail	Information.Center@astrazeneca.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	AZD2693
D.3.2	Product code	[AZD2693]
D.3.4	Pharmaceutical form	Solution for injection/infusion
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.3.9.2	Current sponsor code	AZD2693 Sodium
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	80
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.IMP: 2
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	AZD2693
D.3.2	Product code	[AZD2693]
D.3.4	Pharmaceutical form	Solution for injection/infusion
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.3.9.2	Current sponsor code	AZD2693 Sodium
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	25
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/infusion
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
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-cirrhotic non-alcoholic steatohepatitis with fibrosis

Steatoepatite non alcolica non cirrotica con fibrosi

E.1.1.1

Medical condition in easily understood language

Non-alcoholic steatohepatitis

Steatoepatite non alcolica

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	24.1
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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the effect of AZD2693 versus placebo on histological resolution of NASH in participants with non-cirrhotic NASH with fibrosis (and homozygous for the PNPLA3 rs738409 148M risk allele) after 52
weeks

Valutare l’effetto di AZD2693 rispetto al placebo sulla risoluzione istologica della NASH in pazienti con NASH non cirrotica con fibrosi (e omozigoti per l’allele di rischio 148M di PNPLA3 rs738409) dopo 52 settimane

E.2.2

Secondary objectives of the trial

1. To assess the effects of AZD2693 to placebo on histological fibrosis improvement in participants homozygous for the PNPLA3 rs738409 148M risk allele
2. To assess the effect of AZD2693 versus placebo on = 2-point improvement in NAS in participants homozygous for the PNPLA3 rs738409 148M risk allele
3. To assess the effect of AZD2693 versus placebo on improvement in fibrosis by at least one stage in participants homozygous for the PNPLA3 rs738409 148M risk allele
4. To assess the effect of AZD2693 versus placebo on circulating biomarkers of fibrosis and fibrogenesis in participants homozygous for the PNPLA3 rs738409 148M risk allele
5. To assess safety and tolerability of AZD2693 compared with placebo in participants with non-cirrhotic NASH with fibrosis and carriers of PNPLA3 rs738409 148M risk allele

1. Valutare gli effetti di AZD2693 rispetto al placebo sul miglioramento istologico della fibrosi nei pazienti omozigoti per l’allele di rischio 148M di PNPLA3 rs738409
2. Valutare l’effetto di AZD2693 rispetto al placebo sul miglioramento di =2 punti del NAS nei pazienti omozigoti per l’allele di rischio 148M di PNPLA3 rs738409
3. Valutare l’effetto di AZD2693 rispetto al placebo sul miglioramento della fibrosi di almeno uno stadio nei pazienti omozigoti per l’allele di rischio 148M di PNPLA3 rs738409
4. Valutare l’effetto di AZD2693 rispetto al placebo sui biomarcatori circolanti di fibrosi e fibrogenesi nei pazienti omozigoti per l’allele di rischio 148M di PNPLA3 rs738409
5. Valutare la sicurezza e la tollerabilità di AZD2693 rispetto al placebo in pazienti con NASH non cirrotica con fibrosi portatori dell’allele di rischio 148M di PNPLA3 rs738409

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age
1 Participant must be 18 to 75 years of age (inclusive) at the time of signing the informed consent
Type of Participant and Disease Characteristics
2 Participants who are carriers for the PNPLA3 rs738409 148M risk allele, who have either homozygous or heterozygous G/G or G/C genotypes.
3 Participants with histological evidence of NASH based on central pathologist evaluation of a liver biopsy obtained up to 6 months before randomisation, or during screening, fulfilling both criteria:
(a) Definitive NASH with NAS = 4 with = 1 in each component (ie, steatosis, lobular inflammation, and ballooning).
(b) Presence of fibrosis stage F2 or F3 according to the NASH CRN fibrosis staging system based on central pathologist evaluation

Età
1 I pazienti devono avere tra 18 e 75 anni (compresi) al momento della firma del consenso informato
Tipo di paziente e caratteristiche della malattia
2 Pazienti portatori dell’allele di rischio di PNPLA3 rs738409 148M, che abbiano genotipo omozigote o eterozigote G/G o G/C
3 Pazienti con evidenze istologica di NASH sulla base della valutazione centralizzata di un patologo di una biopsia epatica ottenuta fino a 6 mesi prima della randomizzazione o durante lo screening, che soddisfi entrambi i criteri:
a) NASH definitive con NAS = 4 con = 1 per ogni componente (steatosi, infiammazione lobulare e rigonfiamento).
(b) Presenza di fibrosi di stadio F2 o F3 secondo il sistema di stadiazione della fibrosi del Clinical Research Network (CRN) per NASH sulla base della valutazione centralizzata di un patologo

E.4

Principal exclusion criteria

1 History of liver transplant or current placement on a liver transplant list.
2 Liver disease of other aetiologies (eg, alcoholic steatohepatitis; drug induced, viral or autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; hemochromatosis; alpha-1 antitrypsin deficiency; Wilson's disease)
3 History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy, or variceal bleeding.
4 Historical persistent or pre-existing renal disease marked by eGFR <40 mL/min/1.73 m2 (as defined by Kidney Disease Improving Global Outcomes guidelines).
5 Confirmed platelet count outside the normal range at the screening visit.
6 Any of the following confirmed at the screening visit:
(a) ALT > 5.0 × ULN
(b) TBL > 1.5 mg/dL (TBL > 1.5 mg/dL is allowed if conjugated bilirubin is < 1.5 × ULN)
(c) INR > 1.3
(d) ALP > 1.5 × ULN (unless the ALP elevation is not from hepatic origin as determined by a bone-specific ALP)

1 Anamnesi di trapianto di fegato o presenza attuale sulla lista per il trapianto di fegato
2 Malattia epatica di altra eziologia (ad es. steatoepatite alcolica; epatite indotta da farmaci, virale o autoimmune; cirrosi biliare primitiva; colangite sclerosante primitiva; emocromatosi; deficit di alfa-1 antitripsina; malattia di Wilson)
3 Anamnesi di cirrosi e/o scompenso epatico, inclusa ascite, encefalopatia epatica o sanguinamento da varici
4 Malattia renale persistente o preesistente storica caratterizzata da eGFR <40 mL/min/1,73 m2 (come definito dalle linee guida sui risultati globali per il miglioramento della malattia renale)
5 Conta piastrinica confermata al di fuori del range di normalità alla visita di screening.
6 Uno qualsiasi dei seguenti confermati durante la visita di screening:
(a) ALT > 5.0 × ULN
(b) TBL > 1.5 mg/dL (TBL > 1.5 mg/dL è permesso se la bilirubina coniugata è < 1.5 × ULN)
(c) INR > 1.3
(d) ALP > 1.5 × ULN (a meno che l'aumento di ALP non sia di origine epatica come determinato da un ALP specifico per l'osso)

E.5 End points

E.5.1

Primary end point(s)

The primary objective is to demonstrate superiority of AZD2693 compared to placebo on the resolution of NASH with no worsening of fibrosis after Week 52 in patients homozygous for the PNPLA3 rs738409 148M risk allele.
To support the primary objective, the primary endpoint is
- The resolution of NASH without any worsening of fibrosis (yes/no).
- The resolution of NASH is defined as a ballooning score of 0, inflammation score of 0 to 1 and steatosis score of any degree (from 0 to 3), as assessed by NASH CRN/NAS score.
- Worsening of fibrosis is defined as an increase in the NASH CRN fibrosis score

L’obiettivo primario è dimostrare la superiorità di AZD2693 rispetto al placebo sulla risoluzione della NASH senza peggioramento della fibrosi dopo 52 settimane in pazienti omozigoti per l’allele di rischio 148M di PNPLA3 rs738409.
Per supportare l’obiettivo primario, l’endpoint primario è
- Risoluzione della NASH senza alcun peggioramento della fibrosi (si/no)
- La risoluzione della NASH è definita come punteggio di rigonfiamento pari a 0, punteggio di infiammazione tra 0 e 1 e punteggio di steatosi di ogni grado (da 0 a 3), come valutato dal punteggio NASH CRN/NAS
- Il peggioramento della fibrosi è definito come un aumento nel punteggio NASH CRN per la fibrosi

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 52 of treatment

Settimana 52 del trattamento

E.5.2

Secondary end point(s)

For patients homozygous for the PNPLA3 rs738409 148M risk allele, secondary endpoints are:
• At least one stage of liver fibrosis improvement with no worsening of NASH (yes/no) after 52 weeks (worsening defined as an increase of at least one stage of either lobular inflammation or hepatocyte ballooning according to NASH CRN criteria)
• Proportion of patients with improvement in fibrosis by at least one stage based on biopsy after Week 52
• = 2-point improvement in NAS in patients homozygous for the PNPLA3 rs738409 148M risk allele after 52 weeks

Per pazienti omozigoti per l’allele di rischio 148M di PNPLA3 rs738409, gli endopoint secondari sono:
- Almeno uno stadio di miglioramento della fibrosi epatica senza peggioramento della NASH (si/no) dopo 52 settimane (peggioramento definito come un aumento di almeno uno stadio dell'infiammazione lobulare o del rigonfiamento degli epatociti secondo i criteri NASH CRN)
- Percentuale di pazienti con miglioramento della fibrosi di almeno uno stadio in base alla biopsia dopo la Settimana 52
- Miglioramento =2 punti nel NAS in pazienti omozigoti per l’allele di rischio 148M di PNPLA3 rs738409 dopo 52 settimane

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 52 of treatment

Settimana 52 del 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

Yes

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

Yes

E.6.11

Pharmacogenomic

Yes

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

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

Argentina

Brazil

Chile

China

Colombia

Hong Kong

India

Japan

Korea, Republic of

Malaysia

Mexico

Peru

Philippines

Singapore

Taiwan

Thailand

United States

Viet Nam

Spain

Germany

Italy

Portugal

Turkey

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 the study is defined as the date of the last visit of the last patient in the study or last scheduled procedure shown in the Schedule of Activities for the last patient in the study globally.
A patient is considered to have completed the study if they have completed at least 36 weeks of intervention and a biopsy 2 weeks (+/- 7 days) after last dose received

La conclusione dello studio è definita come la data dell'ultima visita dell'ultimo paziente nello studio o dell'ultima procedura prevista secondo la Schedule of Activities per l'ultimo paziente nello studio a livello globale.
Si considera che un paziente abbia completato lo studio se ha completato almeno 36 settimane di somministrazione e una biopsia 2 settimane (+/- 7 giorni) dopo l'ultima dose ricevuta

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:

286

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

318

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

Nessuno

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

2023-03-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-01-17

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

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IMP with orphan designation in the indication
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