Simvastatin in Preventing Liver Cancer in Patients With Liver Cirrhosis

Statin Therapy to Reduce Disease Progression From Liver Cirrhosis to Cancer

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02968810

Enrollment

Registered

2016-11-21

Start date

2017-06-21

Completion date

2026-07-07

Last updated

2026-09-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cirrhosis, Hepatocellular Carcinoma

Brief summary

This phase II trial studies how well simvastatin works in preventing liver cancer in patients with liver cirrhosis. Simvastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description

PRIMARY OBJECTIVE: I. To evaluate the effect of a simvastatin intervention versus placebo on the change in serum AFP-L3% from baseline to 6 months following treatment initiation in patients with liver cirrhosis who have a current model for end-stage liver disease (MELD) =\< 20. SECONDARY OBJECTIVES: I. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in: Ia. Serum AFP; Ib. Serum IL-6; Ic. Serum deoxycholic acid; Id. Liver stiffness; Ie. Fibrosis 4 index (FIB-4) score; If. MELD score. EXPLORATORY OBJECTIVES: I. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in other: Ia. serum bile acid levels; Ib. serum immune markers. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive simvastatin orally (PO) once daily (QD). Patients also undergo collection of blood on study and computed tomography (CT) scans/magnetic resonance imaging (MRI) throughout the trial. GROUP II: Patients receive placebo PO QD. Patients also undergo collection of blood on study and CT/MRI throughout the trial. In both groups, treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30, 60, and 90 days.

Interventions

PROCEDUREBiospecimen Collection

Undergo collection of blood

PROCEDUREComputed Tomography

Undergo CT

PROCEDUREMagnetic Resonance Imaging

Undergo MRI

OTHERPlacebo Administration

Given PO

OTHERQuestionnaire Administration

Ancillary studies

DRUGSimvastatin

Given PO

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Confirmed diagnosis of liver cirrhosis assessed by the presence of clinical signs, symptoms, body imaging (ultrasound, computed tomography \[CT\], or magnetic resonance imaging \[MRI\]), or liver biopsy * Age \>= 18 years * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%) * Leukocytes \>= 2,500/microliter * Absolute neutrophil count \>= 1,500/microliter * Platelets \>= 50,000/microliter * Hemoglobin \>= 8 g/dL * Total bilirubin =\< 3 x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 5 x institutional ULN * Creatinine =\< 1.5 x institutional ULN * Women who are able to become pregnant must have a confirmed negative pregnancy test result prior to enrollment; women \>= 50 years of age who have not had a menstrual period in the past year; and women who have had a hysterectomy, both ovaries removed, or a tubal ligation; will not be required to have a pregnancy test * The effects of simvastatin on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women who are able to become pregnant must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately * Ability to understand and the willingness to sign a written informed consent document and medical release * Willing and able to comply with trial protocol and follow-up * Have had an abdominal imaging test (CT, MRI, or ultrasound) within the past 18 months

Exclusion criteria

* Prior or current use of statin medication * Current systemic use of medications known to interact with statins and potentially increase toxicity, including gemfibrozil, cyclosporine, danazol, lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine, strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, human immunodeficiency virus \[HIV\] protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, or cobicistat-containing products), or strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, nafcillin) * History of adverse effects, intolerance, or allergic reactions attributed to compounds of similar chemical or biologic composition to simvastatin (i.e., other statin medications) * Current use of any other investigational agents * Women who are pregnant or breastfeeding; pregnant women are excluded from this study because simvastatin is a lipid-lowering agent with the potential for teratogenic or abortifacient effects; it is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with simvastatin, breastfeeding should be discontinued if the mother is treated with simvastatin * Prior liver transplant * Prior known or suspected hepatocellular carcinoma * Prior cholangiocarcinoma * Model for end-stage liver disease (MELD) \> 20 * Any lab results that do not meet inclusion criteria after the Screen 1 blood tests * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * History of chronic myopathy * Prior germ cell cancer * History of active malignancy within the past 5 years (excluding basal/squamous cell skin cancer or prostate cancer with a Gleason score 6 or less) * Known active infection with HIV * Medical contraindications to blood draw (e.g., hemophilia) * Concurrent illness which in the opinion of the investigators would compromise either the patient or the integrity of the data * Current excessive alcohol consumption (average alcohol consumption of more than 5 drinks per day)

Design outcomes

Primary

Measure	Time frame	Description
Change in Serum AFP-L3%	Baseline to 6 months	Assessed by liquid-phase binding assay. Mean AFP-L3% difference calculated including all participants imputing undetectable values with 0.5%

Secondary

Measure	Time frame	Description
Change in Serum AFP	Baseline to 6 months	Assessed by liquid-phase binding assay. Mean difference in AFP, a glycoform produced by malignant liver cells.
Change in Serum IL-6	Baseline to 6 months	Mean difference in IL-6 (interleukin-6) NPX (normalized protein expression).
Change in Serum Deoxycholic Acid	Baseline to 6 months	Assessed by liquid chromatography coupled with mass spectrometry. Median difference in serum DCA (deoxycholic acid), a secondary bile acid.
Change in Liver Stiffness	Baseline to 6 months	Assessed by liver elastography. Fibroscan score from a fibroscan examination (a non-invasive measurement of liver fibrosis). A test result of greater than 20kPa is generally associated with an increased HCC risk. Mean difference in liver stiffness.
Change in Fibrosis 4 Index Score	Baseline to 6 months	The Fib-4 index is a non-invasive measure of liver stiffness. A high score (FIB4 ≥ 3.25) and low score is (FIB4 \< 1.3) The FIB-4 index is calculated as follows: FIB-4 = (Age × AST (U/L)) ÷ (PLT (109/L) × (√ ALT (U/L)). Change in mean difference.
Change in Model for End-Stage Liver Disease Score	Baseline to 6 months	The Model for End-Stage Liver Disease (MELD) is a validated predictor of survival among different populations of patients with advanced liver disease. MELD = 9.57 x ln(creatinine \[mg/dL\]) + 3.78 x ln(total bilirubin \[mg/dL\]) + 11.2 x ln(INR) + 6.43. Scores range from 6 (low/ less liver disease) to 40 (high/severe liver disease). Change in mean difference.

Countries

Puerto Rico, United States

Contacts

PRINCIPAL_INVESTIGATORMarc T Goodman

Northwestern University

Participant flow

Pre-assignment details

59 participants were randomized. 52 out of 59 participants started study agent.

Participants by arm

Arm	Count
Group I (Simvastatin) Patients receive simvastatin PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity.	28
Group II (Placebo) Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity.	24
Total	52

Baseline characteristics

Characteristic	Group I (Simvastatin)	Total	Group II (Placebo)
Age, Continuous	58 years STANDARD_DEVIATION 9	59 years STANDARD_DEVIATION 8.3	59 years STANDARD_DEVIATION 7.4
Ethnicity (NIH/OMB) Hispanic or Latino	12 Participants	25 Participants	13 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	15 Participants	26 Participants	11 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Black or African American	3 Participants	8 Participants	5 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	24 Participants	43 Participants	19 Participants
Region of Enrollment Puerto Rico	4 participants	7 participants	3 participants
Region of Enrollment United States	24 participants	45 participants	21 participants
Sex: Female, Male Female	11 Participants	22 Participants	11 Participants
Sex: Female, Male Male	17 Participants	30 Participants	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 28	0 / 24
other Total, other adverse events	24 / 28	24 / 24
serious Total, serious adverse events	3 / 28	3 / 24

Outcome results

Primary

Change in Serum AFP-L3%

Assessed by liquid-phase binding assay. Mean AFP-L3% difference calculated including all participants imputing undetectable values with 0.5%