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Clinical Trial Results:
Double-blind, randomized, placebo-controlled, phase II dose-finding study comparing different doses of norursodeoxycholic acid capsules with placebo in the treatment of non-alcoholic fatty liver disease (NAFLD)

Summary
EudraCT number	2013-004605-38
Trial protocol	DE AT
Global end of trial date	20 Sep 2016

Results information
Results version number	v1
This version publication date	26 Jan 2019
First version publication date	26 Jan 2019
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

NUC-4/NAS

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Dr. Falk Pharma GmbH

Sponsor organisation address

Leinenweberstrasse 5, Freiburg, Germany, 79108

Public contact

Dept. of Clin. Res. & Development, Dr. Falk Pharma GmbH, 0049 76115140, zentrale@drfalkpharma.de

Scientific contact

Dept. of Clin. Res. & Development, Dr. Falk Pharma GmbH, 0049 76115140, zentrale@drfalkpharma.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Feb 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

20 Sep 2016

Global end of trial reached?

Yes

Global end of trial date

20 Sep 2016

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of two doses of norursodeoxycholic acid (norUDCA) vs. placebo for the treatment of NAFLD with or without diabetes mellitus type 2

Protection of trial subjects

Close supervision of subjects by implementing interim visits every 14 days during the first 4 weeks of treatment and every 4 weeks up to the Follow- Visit at Week 16 to guarantee their safety and wellbeing. Prior to recruitment of patients all relevant documents of the clinical study were submitted and approved by the Independent Ethics Committees (IECs) responsible for the participating investigators. Written consent documents embodied the elements of informed consent as described in the Declaration of Helsinki, the ICH Guidelines for Good Clinical Practice (GCP) and were in accordance with all applicable laws and regulations. The informed consent form and patient information sheet described the planned and permitted uses, transfers and disclosures of the patient's personal data and personal health information for purposes of conducting the study. The informed consent form and the patient information sheet further explained the nature of the study, its objectives and potential risks and benefits as well as the date informed consent was given. Before being enrolled in the clinical trial, every patient was informed that participation in this trial was voluntary and that he/she could withdraw from the study at any time without giving a reason and without having to fear any loss in his/her medical care. The patient’s consent was obtained in writing before the start of the study. By signing the informed consent, the patient declared that he/she was participating voluntarily and intended to follow the study protocol instructions and the instructions of the investigator and to answer the questions asked during the course of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Mar 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 37

Country: Number of subjects enrolled

Germany: 161

Worldwide total number of subjects

198

EEA total number of subjects

198

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

186

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 200 patients were enrolled into the study in Austria and Germany from March 2015 to September 2016.

Screening details

Screening Criteria: 1. Signed Informed Consent 2. Age ≥ 18 years 3. NAFLD 4. ALT >0.8 ULN. In total, 282 patients were screened. Thereof 200 patients were randomised and 198 patients received at least one dose of study medication and were included in the safety set and full analysis set (FAS) .

Period 1 title

Treatment Phase (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Arm A

Arm description

Norursodeoxycholic acid 1500 mg once daily (6 norUDCA capsules à 250 mg)

Arm type

Experimental

Investigational medicinal product name

Norursodeoxycholic acid 1500 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Norursodeoxycholic acid 1500 mg once daily (6 norUDCA capsules à 250 mg)

Arm B

Arm description

Norursodeoxycholic acid 500 mg once daily (2 norUDCA capsules à 250 mg and 4 placebo capsules à 250 mg)

Arm type

Experimental

Investigational medicinal product name

Norursodeoxycholic acid 500 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Norursodeoxycholic acid 500 mg once daily (2 norUDCA capsules à 250 mg and 4 placebo capsules à 250 mg)

Arm C

Arm description

6 placebo capsules à 250 mg once daily

Arm type

Placebo

Investigational medicinal product name

6 placebo capsules à 250 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

6 placebo capsules à 250 mg once daily

Number of subjects in period 1	Arm A	Arm B	Arm C
Started	67	67	64
Completed	60	64	61
Not completed	7	3	3
other reasons	2	-	-
Adverse event, non-fatal	5	2	2
patient wish	-	1	1

Baseline characteristics

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Reporting group title

Treatment Phase (overall period)

Reporting group description

Reporting group values	Treatment Phase (overall period)	Total
Number of subjects	198	198
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	186	186
From 65-84 years	12	12
85 years and over	0	0
Age continuous
Units: years
arithmetic mean (full range (min-max))	47.5 (19 to 73)	-
Gender categorical
Units: Subjects
Female	75	75
Male	123	123

End points

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Reporting group title

Arm A

Reporting group description

Norursodeoxycholic acid 1500 mg once daily (6 norUDCA capsules à 250 mg)

Reporting group title

Arm B

Reporting group description

Norursodeoxycholic acid 500 mg once daily (2 norUDCA capsules à 250 mg and 4 placebo capsules à 250 mg)

Reporting group title

Arm C

Reporting group description

6 placebo capsules à 250 mg once daily

Primary: Relative change in ALT

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End point title

Relative change in ALT

End point description

Relative change (%) in ALT between V2 and V6-LOCF

End point type

Primary

End point timeframe

Between V2 (Baseline) and V6-LOCF

End point values	Arm A	Arm B	Arm C
Number of subjects analysed	67	67	64
Units: percent
arithmetic mean (standard deviation)	-17.4 ( 26.1 )	-4.2 ( 37.5 )	10.4 ( 51.0 )

normal approximation test for comparing two rates

Statistical analysis description

the inverse normal method of combining the p-values of the normal approximation test for comparing two rates.

Comparison groups

Arm A v Arm B v Arm C

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001 ^[2]

Method

approx.-test for comparing two rates

Confidence interval

Notes
[1] - For estimating the treatment effect, the difference between the mean relative ALT change (%) from baseline in the respective treatment group and in the placebo group is provided together with the corresponding two-sided 95% repeated confidence interal (RCI).
[2] - Difference between means of Arm A (N1500) and Arm C (Placebo) was -27.8 (overall p-value < 0.0001; 95%-RCI [-34.7,-14.4]). Difference between means of Arm B (N500) and Arm C (Placebo) was -14.6 (overall p-value = 0.0905; 95%-RCI [-20.7, 3.59]).

Secondary: Number of patients with ALT ≤ 0.8 ULN at V6-LOCF

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End point title

Number of patients with ALT ≤ 0.8 ULN at V6-LOCF

End point description

End point type

Secondary

End point timeframe

proportion of patients with ALT ≤ 0.8 ULN at V6-LOCF

End point values	Arm A	Arm B	Arm C
Number of subjects analysed	57	61	58
Units: patients
number (not applicable)	10	9	3

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were assessed at all interim visits (Week 2, 4, 8) to final visit of individual patient or Week 12 respectively. There was a 4-week follow-up after EOT.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Arm A

Reporting group description

Norursodeoxycholic acid 1500 mg once daily (6 norUDCA capsules à 250 mg)

Reporting group title

Arm B

Reporting group description

Norursodeoxycholic acid 500 mg once daily (2 norUDCA capsules à 250 mg and 4 placebo capsules à 250 mg)

Reporting group title

Arm C

Reporting group description

6 placebo capsules à 250 mg once daily

Serious adverse events	Arm A	Arm B	Arm C
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 67 (1.49%)	2 / 67 (2.99%)	3 / 64 (4.69%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer recurrent
subjects affected / exposed	0 / 67 (0.00%)	0 / 67 (0.00%)	1 / 64 (1.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Joint dislocation
subjects affected / exposed	0 / 67 (0.00%)	0 / 67 (0.00%)	1 / 64 (1.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Ventricular extrasystoles
subjects affected / exposed	1 / 67 (1.49%)	0 / 67 (0.00%)	0 / 64 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Postmenopausal haemorrhage
subjects affected / exposed	0 / 67 (0.00%)	1 / 67 (1.49%)	0 / 64 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess neck
subjects affected / exposed	0 / 67 (0.00%)	1 / 67 (1.49%)	0 / 64 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 67 (0.00%)	0 / 67 (0.00%)	1 / 64 (1.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Arm A	Arm B	Arm C
Total subjects affected by non serious adverse events
subjects affected / exposed	46 / 67 (68.66%)	44 / 67 (65.67%)	45 / 64 (70.31%)
Nervous system disorders
Headache
subjects affected / exposed	10 / 67 (14.93%)	6 / 67 (8.96%)	3 / 64 (4.69%)
occurrences all number	11	6	3
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 67 (0.00%)	5 / 67 (7.46%)	4 / 64 (6.25%)
occurrences all number	0	5	4
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	7 / 67 (10.45%)	5 / 67 (7.46%)	6 / 64 (9.38%)
occurrences all number	7	5	7
Nausea
subjects affected / exposed	6 / 67 (8.96%)	1 / 67 (1.49%)	3 / 64 (4.69%)
occurrences all number	7	2	4
Abdominal pain upper
subjects affected / exposed	3 / 67 (4.48%)	6 / 67 (8.96%)	2 / 64 (3.13%)
occurrences all number	3	7	2
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	4 / 67 (5.97%)	0 / 67 (0.00%)	0 / 64 (0.00%)
occurrences all number	4	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	7 / 67 (10.45%)	6 / 67 (8.96%)	6 / 64 (9.38%)
occurrences all number	8	7	6

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
Double-blind, randomized, placebo-controlled, phase II dose-finding study comparing different doses of norursodeoxycholic acid capsules with placebo in the treatment of non-alcoholic fatty liver disease (NAFLD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Relative change in ALT

Primary: Relative change in ALT

Secondary: Number of patients with ALT ≤ 0.8 ULN at V6-LOCF

Secondary: Number of patients with ALT ≤ 0.8 ULN at V6-LOCF

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: Double-blind, randomized, placebo-controlled, phase II dose-finding study comparing different doses of norursodeoxycholic acid capsules with placebo in the treatment of non-alcoholic fatty liver disease (NAFLD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Relative change in ALT

Primary: Relative change in ALT

Secondary: Number of patients with ALT ≤ 0.8 ULN at V6-LOCF

Secondary: Number of patients with ALT ≤ 0.8 ULN at V6-LOCF

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Double-blind, randomized, placebo-controlled, phase II dose-finding study comparing different doses of norursodeoxycholic acid capsules with placebo in the treatment of non-alcoholic fatty liver disease (NAFLD)