Dr. Marshall left UMC and LSU Health Sciences Center.

Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer death among men. While several new treatment options have recently become available, they are costly and have a potential for significant, adverse side effects. Many patients diagnosed with HCC also suffer from underlying liver disease, including cirrhosis. As many as 80-90% of patients diagnosed with HCC also have cirrhosis. Protein-energy malnutrition (PEM) in cirrhosis is as high as 65-90% and significantly increases the risk of morbidity and mortality as well as decreased quality of life.

Branched-chain amino acid (BCAA) supplementation has been extensively studied for usefulness in liver disease, specifically to treat hepatic encephalopathy to and preserve and restore muscle mass. Maintenance of liver function and prevention of PEM are essential for improving outcomes in patients with HCC. Branched-chain amino acid supplementation in HCC has been studied extensively in China & Japan with multiple studies showing improvements in liver function, progression-free survival, and overall survival. Additionally, patients in treatment groups have shown improvement in quality of life indicators. However, these results have yet to be replicated in the United States. Branched-chain amino acid supplementation may be a safe, low-cost approach to improve survival, liver function indicators, and quality of life for patients diagnosed with HCC.

In this study, patients with primary HCC will be randomized to either a treatment group, which will receive standard of care and BCAA supplement or to a control group which will receive standard of care and a maltodextrin placebo. Both groups will receive liver-directed therapy including transarterial chemoembolization (TACE) and thermal ablation. All patients will complete a quality of life survey (FACT-Hep) at each visit.

Products or Devices to be Studied:

Branched Chain Amino Acid anhydrous blend (1250mg valine, 2500mg leucine, 1250mg isoleucine) Pre-assigned IND number: 140871 Holder of the IND (Richard Marshall, MD)

Purpose of the Study:

Aim: To evaluate the effect of branched-chain amino acid (BCAA) supplementation on progression-free survival and overall survival in patients diagnosed with hepatocellular carcinoma (HCC).

Rationale:

Hepatocellular carcinoma (HCC) is the most common adenocarcinoma affecting the liver. Approximately 14 million people are affected globally and the number of cases is expected to increase to 22 million by 2032. In the United States, HCC accounts for 5% of all cancer-related deaths and has a 1-year survival rate of 41.5% and a 5-year survival rate of 16.5%. Although several new treatment options have recently become available, they are expensive and show a strong potential for adverse side effects. Regardless of treatment modality, liver function maintenance is an essential component for improving outcomes in patients with HCC.

The liver functions as a primary site for macronutrient, enzyme, vitamin, bile acid, and heme metabolism as well as the breakdown and excretion of toxic waste products of metabolism. Among the liver's many roles is the production of albumin, a serum protein responsible for maintaining oncotic pressure and the transportation of nutrients throughout the body. Low levels of albumin (hypoalbuminemia) are associated with severe malnutrition and can lead edema due to decreased oncotic pressure. Hepatic tissue damage, tumor formation, and tumor proliferation decreases the liver's functional capacity for executing these processes.

Chronic injury to the hepatocytes can lead to the development of hepatocellular carcinoma. Once developed, tumor cells and stromal cells form a network called the tumor microenvironment which further contributes to tumor proliferation. Treatments to disrupt the microenvironment (e.g. sorafenib) may be successful in reducing fibrosis, liver damage, inflammation, and angiogenesis. These treatments are not without serious side effects including: myocardial infarction, bleeding problems, bowel perforation, and hypertension to name a few.

Therapeutic approaches to manage symptoms associated with HCC include late evening snacks and protein supplementation. The rationale purports that improvements in nutritional quality will alleviate catabolic stress, thereby reducing risks of associated complications of malnutrition including: protein energy malnutrition, hypoalbuminemia, and hepatic encephalopathy. Further, the branched-chain amino acids (BCAA) valine, leucine, and isoleucine may act on the same signaling pathways of chemotherapeutic pharmaceuticals in addition to improving nutritional status in patients with HCC.

Recently, BCAA supplementation has been explored as a possible treatment for hepatocellular carcinoma in conjunction with standard of care in Japan and China. A recent meta-analysis of clinical studies from China and Japan supports the safety of BCAA supplementation and the possible benefit of improving liver functional reserves and quality of life. However, significant differences in study designs and BCAA doses make inferring conclusions from these studies difficult. Moreover, studies don't adequately control for differences in dietary intake between treatment groups which may skew results. To date, no clinical trials have been conducted in the United States that examine the effects of BCAA supplementation in patients with HCC. The purpose of this study is to examine the safety, efficacy, and feasibility of BCAA supplementation in patients with HCC who undergo locoregional therapies.

Study Procedures:

Current standard of care for hepatocellular carcinoma consists of physician monitoring following liver directed therapy and does not include any nutrition or dietary intervention beyond meeting basic nutritional needs. The study procedures differ from standard of care only by the addition of either a BCAA supplement or maltodextrin placebo, administration of a quality of life survey (FACT-Hep), and a personalized diet prescription.

To ensure protein and energy intake is equivalent between groups, individualized diets will be calculated by the dietitian based on current height, weight, and stress factors for those in both arms of the study. The corresponding meal plan will be administered by the research pharmacist. The intervention group receiving 10g of BCAA daily will receive a meal plan that reflects a protein deficit of 10g below estimated needs (which will be covered by the BCAA supplement).

Subjects:

Forty subjects will be enrolled. Patients who are seeking treatment in the interventional radiology department at University Medical Center (UMC) will comprise the sample.

Duration of the Study:

Enrollment of the full sample will take approximately 36 months and each participant will be followed for 12 months after enrollment and initiation of the treatment. This study would conclude approximately 48 months following first enrollment. Each individual's participation in the study will be 12-14 months following their enrollment.

Implementation Summary:

Patients will be educated about the study by an interventional radiologist and oncology dietitian during their first visit to the interventional radiology clinic at UMC. After providing informed consent to participate in the study, patients will be immediately started on their dietary supplement (BCAA or placebo) for two weeks. BCAA supplements will be dispensed a UMC pharmacist. Patients will then have a brief hospital stay at UMC (typically ranging 6-24 hours) to receive their TACE and/or ablation procedure. All patients will be assessed by an interventional radiologist or nurse practitioner prior to discharge, and those undergoing a TACE procedure will also have a comprehensive metabolic panel (CMP) drawn. After discharge patients will have a one month, three month, 6 month, 9 month, and 12 month follow up in the interventional radiology clinic where they will meet with the physician and dietitian. A detailed list of procedures is provided below. Patients may require additional visits if it is determined that they need additional local therapies (repeat TACE and/or Ablation).

Risks of Interventions:

Branched-chain amino acid supplementation. Risks: Based on data from prior studies, participants receiving BCAA supplementation protocol may experience nausea, vomiting, abdominal pain, diarrhea or hypertension.

Maltodextrin supplementation. Risks: Maltodextrin is a sugar. Consuming maltodextrin may cause a temporary rise in blood sugar. However the amounts consumed for this study will be very small. There are no known risks associated with its use. Maltodextrin is affirmed by the FDA as GRAS per Title 21 of the Code of Federal Regulations Section 184.1444.

Fact-Hep questionnaire. Risks: there are no known risks to questioning about health-related quality of life.

Data Safety Monitoring:

Definition:

Serious adverse event (SAE): events including death, a life-threatening adverse experience, inpatient hospitalization, prolongation of existing hospitalization, and persistent or significant disability or incapacity.

Adverse event (AE): any health-related, unfavorable or unintended medical occurrence that happens throughout study participation. Examples of adverse events include but are not limited to the following:

A clinically significant laboratory or clinical test result. An event that results in missing a study visit. An event that requires a visit to a physician. An event that occurs as a result of a study procedure. Unanticipated or untoward medical events that may be study related.

Monitoring Plan:

Adverse events will be reported to the principal investigator as they are collected from the participant. Adverse event data will be analyzed quarterly, whereas serious or life-threatening adverse events will necessitate immediate reporting and follow-up. It is anticipated that most adverse events will be mild and the participant will be able to resume activities within one to two days of reporting the event.

SAEs that are unanticipated, serious, and possibly related to the study intervention will be reported to the IRB and FDA. Unexpected problems involving risks to participants or others include incidents only if the incident is unexpected, related or possibly related to participation in the research, and indicated that subjects or others are at a greater risk of harm than was previously known or recognized. A SAE will result in the unblinding of the participant and will be reported to the IRB and FDA per CFR § 312.32(c)(5). Any action resulting in unblinding, and/or a temporary or permanent suspension of this study (e.g., IRB actions, or actions by the PI and/or co-investigators) will be reported to the appropriate officials.

Aggregate comparisons of AE and SAE between study arms will occur after 50% of the participants are enrolled. If there is evidence of a significant, clinically relevant difference in SAE between groups, the study will be unblinded; and in the event the BCAA group experiences significantly fewer SAEs, the placebo group will be offered the BCAA supplement. Conversely, if the BCAA group experiences significantly more SAEs, the supplementation will be terminated and follow-up will continue as planned.

Statistical Analysis:

A total of 40 subjects will be recruited (20 in each intervention and control group). Sample size was determined to achieve a power of 0.8 for a two-sided test (α = 0.05) for a balanced study design. The results of the power analysis indicate that this can be achieved with a sample ranging from 13-21 patients in each arm with the assumption that 1 year mortality will be 41.5% in the control group (mortality rate derived from epidemiological data) and a mortality rate ranging from 85 - 95% in the intervention group. Progression-free survival and overall survival will be examined using survival regression analyses while controlling for relevant covariates (age, demographics, etc.). Quality of life, Child Pugh score, and biomarkers of liver function will be examined using repeated measures ANOVA with contrasts between the treatment groups. Tolerability of the BCAA supplement will be assessed by examining the number of adverse effects reported by participants. The severity of the adverse events will be assessed by the physician and frequency differences between groups will be compared using Χ² test statistic.

Inclusion Criteria:

• Have been diagnosed with HCC and deemed a candidate for nonsurgical local therapy (TACE and/or percutaneous ablation)
• Have a Child-Pugh score < 6
• Are at least 18 years of age or older
• Otherwise healthy adults
• Provide written consent to participate

Exclusion Criteria:

• Have a diagnosis of renal failure
• Have a Child-Pugh score > 6
• Consume > 60g alcohol intake per day
• Have been diagnosed with branched-chain ketoaciduria (maple syrup urine disease)
• Have hepatic encephalopathy
• Have been diagnosed with a medical condition that warrants a low-protein diet
• Are currently taking insulin or metformin
• Pregnant women
• Younger than 18 years of age
• Are unable to provide consent
• Are incarcerated

Individual participant data may be shared in collaboration with the current investigators for future studies in which branched chain amino acids for treatment of liver disease are studied in a similar manner to this protocol. All collected data may be made available after local Institutional Review Board authorization, de-identification through a secure method of data transfer (encrypted file sharing) and kept on a secure server.

The time frame for data sharing will begin after initial publication and will extend for 5 years.

After this point, data will be purged from secured servers and will no longer be available for sharing.

A request for data will be made through the principal investigator of this study, who is responsible for data storage. Requests will be made to local Institutional Review Boards prior to de-identified data release.