Clinical Trials Register

Summary
EudraCT Number:	2007-002114-19
Sponsor's Protocol Code Number:	9831-CL-0301
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-04-08
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2007-002114-19

A.3

Full title of the trial

A phase II, randomized, double-blind, parallel-group, placebo-controlled, 12-week treatment, adaptive proof-of-principle study of twice daily oral dosing of a novel PDE4 inhibitor (ASP9831) in subjects with non-alcoholic steatohepatitis (NASH)

A.3.2

Name or abbreviated title of the trial where available

ASTER

A.4.1

Sponsor's protocol code number

9831-CL-0301

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Astellas Pharma Europe B.V.
B.1.3.4	Country	Netherlands
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	ASP9831
D.3.2	Product code	ASP9831
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ASP9831
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	5
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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	ASP9831
D.3.2	Product code	ASP9831
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ASP9831
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	20
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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: 3
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	ASP9831
D.3.2	Product code	ASP9831
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ASP9831
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	40
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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

Non-alcoholic Steatohepatitis (NASH)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10053219
E.1.2	Term	Non-alcoholic steatohepatitis

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part 1: Objective:
To explore exposure to ASP9831 in patients with Non-alcoholic Steatohepatitis (NASH) and to compare the data with healthy volunteer data

Part 2: Primary objective:
To study the effect of a 12 week treatment with two dose levels of ASP9831 compared to placebo on liver injury by assessing serum levels of Alanine Aminotransferase (ALT) in subjects with NASH

E.2.2

Secondary objectives of the trial

Part 2: Secondary objectives:
• To study the safety of two dose levels of ASP9831 compared to placebo in subjects with NASH
• To perform an exploratory analysis of
o the effect of ASP9831 on hepatic steatosis
o the effect of ASP9831 on liver inflammation and vascular damage
o the effect of ASP9831 on other liver injury markers
o the effect of ASP9831 on liver fibrosis
o the effect of ASP9831 on insulin resistance
o the effect of ASP9831 on clinical symptoms
o the pharmacokinetics and the pharmacokinetic / pharmacodynamic relationships of ASP9831 in the study population

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria Part 1
1. Subject has signed written informed consent prior to screening
2. Subject is male or female and 18 years of age or above
3. For Part 1a: Subject has NASH, fibrosis stage F3 (zone 3 perisinusoidal / pericellular
fibrosis and portal fibrosis with focal or extensive bridging fibrosis) histologically
confirmed by a liver biopsy performed within 1 year prior to first dose.
For Part 1b:
Subject has NASH, fibrosis stage F0 - F3, histologically confirmed by a liver biopsy
performed within 1 year prior to randomization
4. Subject has serum ALT levels at screening below 300 U/l according to central laboratory analysis
5. Subject has had elevated serum ALT levels on two occasions tested within 1 year prior to screening according to local laboratory normal ranges.

Inclusion Criteria Part 2
1. Subject has signed written informed consent prior to screening
2. Subject is male or female and 18 years of age or above
3. Subject has NASH, fibrosis stage F0 - F3, histologically confirmed by a liver biopsy
performed within 1 year prior to randomization
4. Subject has elevated serum ALT levels at screening of at least 1.5x the upper limit of
normal range with a maximum of 300 U/l according to central laboratory analysis
5. Subject has had elevated serum ALT levels >1.5 ULN or > 60 IU/L (local laboratory) on one occasion in the past 6 months and no documented normal value in the past year.

E.4

Principal exclusion criteria

1. Subject is diagnosed with hepatic cirrhosis
2. Subject has confirmed positive HCV and / or positive HBV serology
3. Subject has known genetic or secondary hemochromatosis
4. Subject has other known cause of liver disease (autoimmune, viral, genetic, drug induced, alcoholic liver disease or storage disease) or drug-induced hepatotoxicity
5. Subject has an unstable metabolic condition i.e.; weight change > 5% in the 6 months prior to screening and / or diagnosis of diabetes mellitus type 2 within 4 months prior to screening and / or initiation and subsequent continuous use of anti-diabetic drugs (including insulin sensitizing agents), anti-hypertensives and/or lipid lowering drugs within 4 months prior to screening
6. Subject has uncontrolled diabetes mellitus type 2, i.e. HbA1c > 8.5%
7. Subject suffers from clinically significant gastrointestinal disease, or has a history of inflammatory bowel disease (Crohn’s disease, ulcerative colitis and undetermined inflammatory colitis) or has a currently symptomatic gastric ulcer or erosive gastritis
8. Irritable bowel syndrome
9. Subject has known lipodystrophy
10. Subject has had a malignancy in the last 10 years, except for adequately treated basal or squamous cell carcinoma of the skin
11. Subject has known HIV infection
12. Subject has had previous bowel resection
13. Subject has a positive history of tuberculosis or a positive PPD skin test which is not explained by previous BCG vaccination
14. Subject has any other disorder that is uncontrolled by therapy and clinically significant as deemed relevant by the investigator
15. Subject has a history of excessive alcohol abuse within 5 years prior to screening or a current average alcohol intake of more than 20 g/day (2 units) for females or more than
30 g/day (3 units) for males
16. Female subject is pregnant, lactating or pre-menopausal with positive serum pregnancy test (hCG) or has an intention of becoming pregnant and / or does not use a medically acceptable method of birth control.**
17. Subject has used drugs associated with steatohepatitis within 6 months prior to screening (corticosteroids, high dose estrogens, methotrexate, amiodarone, anti-HIV drugs, tamoxifen)
18. Subject has used other PDE4 inhibitors within 6 months prior to screening
19. Subject started or changed the dose of one or more of the following drugs / food supplements within 1 month before randomization: insulin sensitizing agents (e.g.
biguanides, thiazolinediones), ursodeoxycholic acid, anti-obesity drugs (e.g. orlistat,
sibutramin, rimonabant), pentoxifylline, phosphatidylcholin, ginseng, selenium, vitamin
C, vitamin E
20. Subject uses concomitant medications which are mainly metabolized by CYP2C8/9 and which have a narrow safety margin (warfarin, phenytoin, paclitaxel and tolbutamide)

E.5 End points

E.5.1

Primary end point(s)

Percentage change in serum ALT at the end of treatment at 12 weeks compared to baseline

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

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

Yes

E.8.1.7.1

Other trial design description

Part 1: open-label

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.8.3

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

Information not present in EudraCT

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

Last scheduled visit of the last patient

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	16
F.4.2	For a multinational trial
F.4.2.1	In the EEA	75
F.4.2.2	In the whole clinical trial	105

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

2008-04-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-11-28

P. End of Trial
P.	End of Trial Status	Completed

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