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Clinical Trial Results:
Efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis to prevent ACLF development: a multicenter, double-blind, placebo controlled randomized clinical trial (LIVERHOPE_EFFICACY).

Summary
EudraCT number	2018-001698-25
Trial protocol	ES NL FR GB DE BE IT
Global end of trial date	01 Dec 2022

Results information
Results version number	v1(current)
This version publication date	23 Oct 2025
First version publication date	23 Oct 2025
Other versions

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

LIVERHOPE_EFFICACY

ISRCTN number

US NCT number

NCT03780673

WHO universal trial number (UTN)

Sponsor organisation name

IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer)

Sponsor organisation address

Rosselló, 149 , Barcelona, Spain, 08036

Public contact

Pere Ginés, Hospital Clínic, +34 9322754001713, pgines@clinic.cat

Scientific contact

Pere Ginés, Hospital Clínic, +34 9322754001713, pgines@clinic.cat

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

01 Dec 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Dec 2022

Global end of trial reached?

Yes

Global end of trial date

01 Dec 2022

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of oral administration of Simvastatin plus Rifaximin in halting the progression of decompensated cirrhosis as assessed by the time to first incidence of ACLF during treatment period.

Protection of trial subjects

All participants will provide written informed consent before any study procedures. The trial complies with the Declaration of Helsinki, ICH-GCP, and EU regulations. Ethics Committee and Competent Authority approvals are obtained. Patient confidentiality and data protection are ensured per GDPR. Insurance covers trial-related injuries.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Jan 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 14

Country: Number of subjects enrolled

Spain: 95

Country: Number of subjects enrolled

United Kingdom: 12

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Italy: 91

Worldwide total number of subjects

254

EEA total number of subjects

242

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)

254

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study recruited 254 patients with decompensated cirrhosis across 14 European hospitals between January 2019 and December 2021. Patients were randomized to receive simvastatin plus rifaximin or placebo for 12 months.

Screening details

772 patients were screened for eligibility. Inclusion criteria included age ≥18 and Child-Pugh class B or C cirrhosis. Key exclusions were ACLF at baseline, severe liver impairment, hepatocellular carcinoma, or ongoing statin/rifaximin therapy.

Period 1 title

Randomisation

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst

Are arms mutually exclusive

Yes

Simvastatin plus Rifaximin

Arm description

A total of 126 patients were randomized to receive simvastatin (20 mg/day) plus rifaximin (1200 mg/day) for 12 months. Of these, 117 initiated treatment and were included in the primary analysis.

Arm type

Experimental

Investigational medicinal product name

Simvastatin 20 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The first cohort will receive one 20 mg tablet of simvastatin every 24 hours at night.

Investigational medicinal product name

Rifaximin 400 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The first cohort will receive one 400 mg tablet of rifaximin every 8 hours.

Placebo

Arm description

A total of 128 patients were randomized to receive placebo for 12 months. Of these, 120 initiated treatment and were included in the primary analysis.

Arm type

Placebo

Investigational medicinal product name

Simvastatin Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The second cohort will receive one tablet of placebo of simvastatin every 24 hours at night.

Investigational medicinal product name

Rifaximin Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The second cohort will receive one tablet of placebo of rifaximin every 8 hours.

Number of subjects in period 1	Simvastatin plus Rifaximin	Placebo
Started	126	128
Completed	117	120
Not completed	9	8
Consent withdrawn by subject	1	2
Protocol deviation	8	6

Period 2 title

Primary analysis population

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Simvastatin plus Rifaximin

Arm description

This arm includes 117 patients who initiated treatment with simvastatin plus rifaximin and were included in the primary analysis. Baseline characteristics and outcomes are reported for this population. 81 patients completed the study.

Arm type

Experimental

Investigational medicinal product name

Simvastatin 20 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The first cohort will receive one 20 mg tablet of simvastatin every 24 hours at night.

Investigational medicinal product name

Rifaximin 400 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The first cohort will receive one 400 mg tablet of rifaximin every 8 hours.

Placebo

Arm description

This arm includes 120 patients who initiated treatment with placebo and were included in the primary analysis. Baseline characteristics and outcomes are reported for this population. 69 patients completed the study.

Arm type

Placebo

Investigational medicinal product name

Simvastatin Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The second cohort will receive one tablet of placebo of simvastatin every 24 hours at night.

Investigational medicinal product name

Rifaximin Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The second cohort will receive one tablet of placebo of rifaximin every 8 hours.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: The first period (“Randomisation”) includes all randomized patients (n=254), regardless of whether they initiated treatment. However, the baseline period was defined as the second period (“Primary analysis population”), which includes only the 237 patients who started treatment and for whom baseline characteristics were collected. This structure reflects the actual conduct of the trial and ensures accurate reporting of baseline data.

Number of subjects in period 2 ^[2]	Simvastatin plus Rifaximin	Placebo
Started	117	120
Completed	81	69
Not completed	36	51
Consent withdrawn by subject	8	10
Physician decision	3	6
Adverse event, non-fatal	17	23
Other	-	1
Lost to follow-up	2	-
Had transplant	3	8
Protocol deviation	3	3

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The trial randomized 254 patients, but only 237 initiated treatment and were included in the primary analysis. Baseline characteristics are reported exclusively for these 237 patients, as they represent the population that received at least one dose of study medication. The remaining 17 patients were excluded prior to treatment initiation due to protocol violations or other eligibility issues, and therefore do not have baseline data available.

Baseline characteristics

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Reporting group title

Simvastatin plus Rifaximin

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	Simvastatin plus Rifaximin	Placebo	Total
Number of subjects	117	120	237
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	58 ( 9 )	56 ( 10 )	-
Gender categorical
Units: Subjects
Female	29	38	67
Male	88	82	170

End points

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Reporting group title

Simvastatin plus Rifaximin

Reporting group description

A total of 126 patients were randomized to receive simvastatin (20 mg/day) plus rifaximin (1200 mg/day) for 12 months. Of these, 117 initiated treatment and were included in the primary analysis.

Reporting group title

Placebo

Reporting group description

A total of 128 patients were randomized to receive placebo for 12 months. Of these, 120 initiated treatment and were included in the primary analysis.

Reporting group title

Simvastatin plus Rifaximin

Reporting group description

Reporting group title

Placebo

Reporting group description

Primary: Time to ACLF in the two groups during follow-up

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End point title

Time to ACLF in the two groups during follow-up

End point description

Efficacy of treatment in halting the progression of decompensated cirrhosis as assessed by time to first ACLF during the treatment period, defined according to criteria by Moreau et al., Gastroenterology 2013. The endpoint is reported as the number of subjects who developed ACLF during the 12-month follow-up.

End point type

Primary

End point timeframe

12 months

End point values	Simvastatin plus Rifaximin	Placebo
Number of subjects analysed	117	120
Units: Subjects
Subjects with ACLF	21	17

Primary endpoint analysis: Time to ACLF

Statistical analysis description

The primary endpoint was analyzed using a Fine and Gray competing risk model, stratified by Child-Pugh class. This method accounts for competing events such as death and liver transplant. Since Fine and Gray is not available in the selection list, “Regression, cox” has been selected as the closest approximation.

Comparison groups

Simvastatin plus Rifaximin v Placebo

Number of subjects included in analysis

237

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.52 ^[2]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

2.34

Notes
[1] - The study aimed to assess whether simvastatin plus rifaximin was superior to placebo in preventing ACLF.
[2] - No statistically significant difference was observed between groups.

Adverse events

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Timeframe for reporting adverse events

12 months (duration of treatment and follow-up)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Simvastatin + Rifaximin

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Simvastatin + Rifaximin	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	44 / 117 (37.61%)	50 / 120 (41.67%)
number of deaths (all causes)	17	17
number of deaths resulting from adverse events	12	13
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial adenocarcinoma
subjects affected / exposed	1 / 117 (0.85%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Injury, poisoning and procedural complications
Craneoencephalic trauma
subjects affected / exposed	1 / 117 (0.85%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Surgical and medical procedures
Transplant
subjects affected / exposed	5 / 117 (4.27%)	12 / 120 (10.00%)
occurrences causally related to treatment / all	0 / 5	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Hypoxic encephalopathy due to stroke
subjects affected / exposed	1 / 117 (0.85%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
General disorders and administration site conditions
Unknown cause of Death
Additional description: Found dead at home and Cause of death not reported
subjects affected / exposed	2 / 117 (1.71%)	2 / 120 (1.67%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 2
Immune system disorders
Neurosarcoidosis
subjects affected / exposed	0 / 117 (0.00%)	1 / 120 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hepatobiliary disorders
ACLF (Acute-on-Chronic Liver Failure)
Additional description: ACLF is a severe decompensation of cirrhosis characterized by failure of one or more organs or systems (including liver, kidney, brain, respiratory, circulatory, and coagulation) and is associated with poor short- and mid-term prognosis. Defined acco
subjects affected / exposed	21 / 117 (17.95%)	17 / 120 (14.17%)
occurrences causally related to treatment / all	21 / 21	17 / 17
deaths causally related to treatment / all	12 / 12	13 / 13
Complications of cirrhosis
Additional description: New ascites, worsening of ascites, hepatic encephalopathy, acute kidney injury,bacterial infection, and variceal bleeding.
subjects affected / exposed	10 / 117 (8.55%)	17 / 120 (14.17%)
occurrences causally related to treatment / all	0 / 111	0 / 132
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis
subjects affected / exposed	3 / 117 (2.56%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Simvastatin + Rifaximin	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	57 / 117 (48.72%)	50 / 120 (41.67%)
Nervous system disorders
Nervous systemdisorders
subjects affected / exposed	14 / 117 (11.97%)	7 / 120 (5.83%)
occurrences all number	18	7
Gastrointestinal disorders
Gastrointestinaldisorders
subjects affected / exposed	35 / 117 (29.91%)	40 / 120 (33.33%)
occurrences all number	53	62
Hepatobiliary disorders
Hepatobiliarydisorders
subjects affected / exposed	44 / 117 (37.61%)	46 / 120 (38.33%)
occurrences all number	85	91
Renal and urinary disorders
Kidney and urinarydisorders
subjects affected / exposed	19 / 117 (16.24%)	21 / 120 (17.50%)
occurrences all number	31	32
Musculoskeletal and connective tissue disorders
Musculoskeletal andconnective tissuedisorders
Additional description: Three patients in the simvastatin plus rifaximin group presented with 1 episode ofrhabdomyolysis (2.5%) vs zero episodes in zero patients in the placebo group.
subjects affected / exposed	32 / 117 (27.35%)	26 / 120 (21.67%)
occurrences all number	39	30
Infections and infestations
Infection
subjects affected / exposed	33 / 117 (28.21%)	33 / 120 (27.50%)
occurrences all number	64	45
Metabolism and nutrition disorders
Metabolism andnutrition disorders
subjects affected / exposed	21 / 117 (17.95%)	19 / 120 (15.83%)
occurrences all number	33	26

More information

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Were there any global substantial amendments to the protocol? Yes

17 Dec 2018

Substantial Amendment No. 1

10 Jan 2020

Substantial Amendment No. 2

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.

Most patients had alcohol-related cirrhosis; findings may not apply to MASLD or viral hepatitis. The statin dose was low, and patients had moderate to severe liver impairment.

http://www.ncbi.nlm.nih.gov/pubmed/39908052

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Clinical trials

Clinical Trial Results:
Efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis to prevent ACLF development: a multicenter, double-blind, placebo controlled randomized clinical trial (LIVERHOPE_EFFICACY).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to ACLF in the two groups during follow-up

Primary: Time to ACLF in the two groups during follow-up

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: Efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis to prevent ACLF development: a multicenter, double-blind, placebo controlled randomized clinical trial (LIVERHOPE_EFFICACY).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to ACLF in the two groups during follow-up

Primary: Time to ACLF in the two groups during follow-up

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis to prevent ACLF development: a multicenter, double-blind, placebo controlled randomized clinical trial (LIVERHOPE_EFFICACY).