Pravastatin Intervention to Delay Hepatocellular Carcinoma Recurrence

• Sponsor: Cedars-Sinai Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03219372
• Collaborator: National Institutes of Health (NIH) (NIH), National Cancer Institute (NCI) (NIH)
• Enrollment: 1
• Location: 1
• Arms: 2
• Actual Duration (Months): 5.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Hepatocellular Carcinoma (HCC) is a major health concern in the United States, particularly among people with liver cirrhosis. Out of every 100 patients with liver cancer, only 18 will survive 5 years or more. While locoregional therapies are utilized in an effort to combat this disease, the recurrence rate of HCC after these therapies are high.

Statins are widely used drugs that lower cholesterol levels. Some studies have suggested that statins lower risk of HCC recurrence, but this possibility has not been studied thoroughly in a clinical trial. This study will examine the effects of pravastatin, a type of statin, on time to HCC recurrence in patients with early stage HCC. It is possible that pravastatin in combination with locoregional therapies may delay or protect against HCC recurrence.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma; Liver Cirrhoses	Drug: Pravastatin Pill; Drug: Placebo Oral Tablet	Phase 2

Detailed Description

To date, there has been a scarcity of clinical trials evaluating the effectiveness of adjuvant therapies in patients with early stage HCC, although it is widely considered an area of highly unmet need.

The objective of this randomized double-blinded, placebo-controlled Phase II trial is to examine the effects of pravastatin use versus placebo after 12 months of treatment on hepatocellular cancer (HCC) recurrence in 130 patients with liver cirrhosis, HCC meeting Milan Criteria or OPTN tumor downstaging criteria for tumor burden, and initial locoregional therapy (LRT) with adequate response.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 1:1 drug versus placebo1:1 drug versus placebo
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: double-blind
• Primary Purpose: Prevention
• Official Title: Pravastatin Intervention to Delay Hepatocellular Carcinoma Recurrence
• Actual Study Start Date: Sep 27, 2018
• Actual Primary Completion Date: Dec 4, 2018
• Actual Study Completion Date: Mar 5, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pravastatin Pill Daily pravastatin (40mg)	Drug: Pravastatin Pill; statin; Other Names: statin
Placebo Comparator: Placebo Oral Tablet Placebo	Drug: Placebo Oral Tablet; placebo; Other Names: placebo

Outcome Measures

Primary Outcome Measures

1. Time to Recurrence [12 months from baseline]

   Mean difference in time (in months) from baseline (study visit 1) to first hepatocellular cancer (HCC) recurrence or HCC death within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo. - HCC recurrence will be confirmed by central expert independent radiographic review.

Secondary Outcome Measures

1. Recurrence Free Survival [12 months from baseline]

   Mean difference in time (in months) from baseline (study visit 1) to first occurrence of a documented hepatocellular cancer (HCC) recurrence within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo. - HCC recurrence will be confirmed by central expert independent radiographic review.

2. Overall Survival [12 months from baseline]

   Mean difference in time (in months) from baseline (study visit 1) to death (for any reason) within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo.

3. Waitlist Drop-off [12 months from baseline]

   Mean difference in time from baseline (study visit 1) to liver transplant waitlist drop-off within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo.

4. Change in Liver Stiffness [12 months from baseline]

   Mean difference in mean change in liver stiffness (as measured by MRE or FibroScan) between baseline (study visit 1) and 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo.

5. Change in Liver Fat Fraction [12 months from baseline]

   Mean difference in within-person change in liver fat fraction (as measured by MRE) between baseline (study visit 1) and 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo.

6. Change in Serum Biomarkers of Monocyte/Macrophage and Stellate Cell Activation [12 months from baseline]

   Mean difference in serum biomarkers including cytokines, chemokines, soluble receptors, and proteins (eg. IL6, TNFα, sTNFRII, IL18BP, sCD163, IL10, IL17, IL-8, CCL17, TGFβ) from baseline (study visit 1) to 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo.

7. Levels of Liver Tissue Markers Related to HCC [12 months from baseline]

   Mean difference in liver tissue markers related to HCC including those in the Wnt/β-catenin pathway (eg. β-catenin, glutamine synthetase) from baseline (study visit 1) to 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥18 years

• Confirmed diagnosis of liver cirrhosis (Child-Pugh A or B) assessed by the presence of clinical signs, symptoms, body imaging, or liver biopsy

• Diagnosis of HCC falling within one of the following criteria prior to LRT. Criteria fulfillment will be confirmed by the Imaging Charter and MedQIA.

1. One lesion ≤ 5 cm or two to three lesions, each ≤ 3 cm.

2. One lesion > 5 cm and ≤ 8 cm.

3. Two or three lesions, of which at least one is > 3 cm and all are ≤ 5 cm each. The sum of all diameters must be ≤ 8 cm.

4. Four or five lesions, each < 3 cm. The sum of all diameters must be ≤ 8 cm.

• Initiation of LRT (according to clinical judgement) within 24 months prior to Screening Visit, with adequate response as determined by Imaging Charter and MedQIA.

• ECOG performance status ≤1 (Karnofsky ≥70%; see Appendix A)

• AST (SGOT) & ALT (SGPT) ≤5 × institutional ULN

• AFP < 400 ng/mL

• Ability to understand and the willingness to sign a written informed consent document and medical release

• Agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; for women who are able to become pregnant.

• Willing and able to comply with trial protocol and follow-up

Exclusion Criteria:

• Current use of statin medication or statin use within 12 months of Screening visit.

• Current systemic use of medications known to interact with statins and potentially increase toxicity, including (e.g., gemfibrozil, cyclosporine, clarithromycin, colchicine, niacin and fibrates).

• History of adverse effects, intolerance, or allergic reactions attributed to compounds of similar chemical or biologic composition to pravastatin (i.e., other statin medications)

• Current use of any other investigational agents

• Women who are pregnant. Women who are able to become pregnant must have a confirmed negative pregnancy test prior to enrollment.

• Women who are breastfeeding. It is not known whether pravastatin 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 pravastatin, breastfeeding should be discontinued if the mother is treated with pravastatin.

• Prior liver transplant

• MELD score ≥30.

• History of chronic myopathy

• Active malignancy within the past 5 years (excluding HCC, basal/squamous cell skin cancer, or prostate cancer with a Gleason score 6 or less)

• Known HIV infection

• Hemophilia

• Concurrent illness which in the opinion of the investigators would compromise either the patient or the integrity of the data

• Concurrent excessive alcohol consumption (average alcohol consumption of more than 5 drinks per day)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048

Sponsors and Collaborators

• Cedars-Sinai Medical Center
• National Institutes of Health (NIH)
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Shehnaz Hussain, PhD, Cedars-Sinai Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 12, 2019
• Informed Consent Form - Jul 22, 2019

More Information

Publications

None provided.

• Responsible Party: Shehnaz Hussain, Associate Professor, Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT03219372
• Other Study ID Numbers: IIT2017-08-HUSSAIN-STATLV; 1R01CA218486-01
• First Posted: Jul 17, 2017
• Last Update Posted: Jan 22, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Cirrhosis; Recurrence; Pravastatin

Study Results

Participant Flow

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
Period Title: Overall Study
STARTED	1	0
COMPLETED	0	0
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet	Total
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.	Total of all reporting groups
Overall Participants	1	0	1
Age (Count of Participants)
<=18 years	0 0%	0 NaN
Between 18 and 65 years	0 0%	0 NaN
>=65 years	1 100%	1 Infinity
Sex: Female, Male (Count of Participants)
Female	0 0%	0 NaN
Male	1 100%	1 Infinity
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 NaN
Not Hispanic or Latino	1 100%	1 Infinity
Unknown or Not Reported	0 0%	0 NaN
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 NaN
Asian	0 0%	0 NaN
Native Hawaiian or Other Pacific Islander	0 0%	0 NaN
Black or African American	1 100%	1 Infinity
White	0 0%	0 NaN
More than one race	0 0%	0 NaN
Unknown or Not Reported	0 0%	0 NaN
Region of Enrollment (participants) [Number]
United States	1 100%	1 Infinity

Outcome Measures

1. Primary Outcome

Title	Time to Recurrence
Description	Mean difference in time (in months) from baseline (study visit 1) to first hepatocellular cancer (HCC) recurrence or HCC death within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo. - HCC recurrence will be confirmed by central expert independent radiographic review.
Time Frame	12 months from baseline

Outcome Measure Data

Analysis Population Description

As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
Measure Participants	0	0

2. Secondary Outcome

Title	Recurrence Free Survival
Description	Mean difference in time (in months) from baseline (study visit 1) to first occurrence of a documented hepatocellular cancer (HCC) recurrence within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo. - HCC recurrence will be confirmed by central expert independent radiographic review.
Time Frame	12 months from baseline

Outcome Measure Data

Analysis Population Description

As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
Measure Participants	0	0

3. Secondary Outcome

Title	Overall Survival
Description	Mean difference in time (in months) from baseline (study visit 1) to death (for any reason) within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo.
Time Frame	12 months from baseline

Outcome Measure Data

Analysis Population Description

As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
Measure Participants	0	0

4. Secondary Outcome

Title	Waitlist Drop-off
Description	Mean difference in time from baseline (study visit 1) to liver transplant waitlist drop-off within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo.
Time Frame	12 months from baseline

Outcome Measure Data

Analysis Population Description

As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
Measure Participants	0	0

5. Secondary Outcome

Title	Change in Liver Stiffness
Description	Mean difference in mean change in liver stiffness (as measured by MRE or FibroScan) between baseline (study visit 1) and 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo.
Time Frame	12 months from baseline

Outcome Measure Data

Analysis Population Description

As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
Measure Participants	0	0

6. Secondary Outcome

Title	Change in Liver Fat Fraction
Description	Mean difference in within-person change in liver fat fraction (as measured by MRE) between baseline (study visit 1) and 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo.
Time Frame	12 months from baseline

Outcome Measure Data

Analysis Population Description

As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
Measure Participants	0	0

7. Secondary Outcome

Title	Change in Serum Biomarkers of Monocyte/Macrophage and Stellate Cell Activation
Description	Mean difference in serum biomarkers including cytokines, chemokines, soluble receptors, and proteins (eg. IL6, TNFα, sTNFRII, IL18BP, sCD163, IL10, IL17, IL-8, CCL17, TGFβ) from baseline (study visit 1) to 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo.
Time Frame	12 months from baseline

Outcome Measure Data

Analysis Population Description

As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
Measure Participants	0	0

8. Secondary Outcome

Title	Levels of Liver Tissue Markers Related to HCC
Description	Mean difference in liver tissue markers related to HCC including those in the Wnt/β-catenin pathway (eg. β-catenin, glutamine synthetase) from baseline (study visit 1) to 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo.
Time Frame	12 months from baseline

Outcome Measure Data

Analysis Population Description

As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.

Arm/Group Title	Pravastatin Pill	Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.	Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events were collected over the 2-month* intervention period (one patient and early withdrawal at Visit 2) and within 90 days after the last administration of the study drug. *Scheduled intervention period for this study was 12 months with 6 study visits.
Adverse Event Reporting Description	Regular investigator assessment, regular laboratory testing, self-reporting.
Arm/Group Title	Pravastatin Pill		Placebo Oral Tablet
Arm/Group Description	Pravastatin 40 mg, daily for 12 months Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.		Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent.
All Cause Mortality
	Pravastatin Pill		Placebo Oral Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)
Serious Adverse Events
	Pravastatin Pill		Placebo Oral Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Pravastatin Pill		Placebo Oral Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)
General disorders
Fatigue	1/1 (100%)	1	0/0 (NaN)	0

Limitations/Caveats

Accrual fell well below target. One subject was randomized to the study and withdrew prior to completion. Outcome measures were not analyzed due to insufficient accrual.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.