<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03285217</url>
  </required_header>
  <id_info>
    <org_study_id>HEPATIC</org_study_id>
    <nct_id>NCT03285217</nct_id>
  </id_info>
  <brief_title>HMB for Denutrition in Patients With Cirrhosis (HEPATIC)</brief_title>
  <acronym>HEPATIC</acronym>
  <official_title>HMB for Denutrition in Patients With Cirrhosis (HEPATIC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto Aragones de Ciencias de la Salud</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Refbio2: Trans-Pyrenean cooperation network for biomedical research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Instituto Aragones de Ciencias de la Salud</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cirrhosis is a late stage of hepatic fibrosis caused by many forms of liver diseases and&#xD;
      conditions, such as hepatitis and chronic alcoholism. The World Health Organization (WHO) has&#xD;
      reported that this condition accounts for 1.8% of all deaths in Europe (170,000 deaths/year).&#xD;
&#xD;
      Patients with cirrhosis are characterized by severe metabolic alterations, which converge in&#xD;
      a malnutritional state. Malnutrition encompasses glucose intolerance, chronic inflammation,&#xD;
      altered gut microbiota, reduced muscle mass (sarcopenia), as well as loss and dysregulation&#xD;
      of adipose tissue (adipopenia). Malnutrition is the most frequent complication that adversely&#xD;
      affects the outcomes of cirrhotic patients. Yet, despite its clinical repercussions and&#xD;
      potential reversibility, there are no effective therapies because our limited understanding&#xD;
      of the mechanisms underlying this altered metabolism.&#xD;
&#xD;
      β-hydroxy β-methylbutyrate (HMB) is a naturally produced substance regarded as safe and&#xD;
      effective in preventing muscle loss during chronic diseases. Previous studies have indicated&#xD;
      some beneficial effects of HMB itself or its parent metabolite, leucine, on adipose tissue,&#xD;
      glucose intolerance, inflammation, and gut microbiota. This study aims to translate those&#xD;
      beneficial effects to cirrhotic patients. The investigators hypothesize that HMB can improve&#xD;
      cirrhosis-related metabolic abnormalities through its pleiotropic effects. The goals of this&#xD;
      study are: i) to perform a randomized clinical trial to evaluate the efficacy of HMB,&#xD;
      administered as nutritional supplementation, on clinical symptoms of cirrhosis.&#xD;
&#xD;
      ii) to uncover the precise metabolic pathways that underlie HMB action, with a special focus&#xD;
      on muscle, adipose tissue, and gut microbiota.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Scientific &amp; technical aspects&#xD;
&#xD;
      State of the art:&#xD;
&#xD;
      Patients with cirrhosis present a chronic inflammatory state and alterations in protein&#xD;
      metabolism. These alterations lead to elevated levels of insulin and catecholamines along&#xD;
      with the development of glucose intolerance and insulin resistance. The reduced availability&#xD;
      of glucose as energy source translates into an accelerated starvation with reduced body fat&#xD;
      mass (adipopenia) and loss of skeletal muscle mass (sarcopenia). This catabolic state reduces&#xD;
      survival and post-liver transplant outcomes in patients with cirrhosis.&#xD;
&#xD;
      Loss of skeletal muscle mass or sarcopenia is the major component of malnutrition in&#xD;
      cirrhosis and occurs in the majority of patients. Impaired ureagenesis and portosystemic&#xD;
      shunting provoke skeletal muscle hyperammonemia which induces up-regulation of myostatin and&#xD;
      increased autophagy, both of which contribute to sarcopenia.&#xD;
&#xD;
      The adipose tissue (AT) regulates energy homeostasis in the body regardless of the obesity&#xD;
      status. Indeed, serum levels of the main adipose-produced cytokines (adipokines) such as&#xD;
      leptin, adiponectin, and resistin have been found to be increased in cirrhotic patients as&#xD;
      liver function worsens. Evidence demonstrated that adiponectin interacts with the&#xD;
      immune/macrophage system and might be of relevance in many liver diseases. Likewise,&#xD;
      hyperinsulinemia and increased tumor necrosis factor (TNF) α levels upregulated the adipose&#xD;
      resistin gene in rat models of liver cirrhosis.&#xD;
&#xD;
      Recently, growing attention has been targeted to the gut microbiota (GM) in the pathogenesis&#xD;
      of gastrointestinal diseases. GM constitutes a symbiotic ecosystem that keeps homeostatic&#xD;
      balance within the human body producing a diverse range of compounds that have a major role&#xD;
      in regulating the activity of distal organs. Recent studies have shown changes in the&#xD;
      relative abundance of microbiota in the stool, colonic mucosa, and saliva of cirrhotic&#xD;
      patients. Therefore, modulation of GM arises as a promising tool to prevent and/or to treat&#xD;
      the development of these liver disorders.&#xD;
&#xD;
      Clinical guidelines recommend to provide adequate amounts of calories and proteins to&#xD;
      cirrhotic patients, either by frequent feeding or via diet supplementation. Consequently,&#xD;
      different high caloric diets have been extensively studied. Yet, few studies have shown&#xD;
      significant benefit of this type of diets in malnourished cirrhotic patients. Protein&#xD;
      supplementation may improve the availability of essential amino acids. However, animal&#xD;
      proteins are enriched in aromatic amino acids that are not metabolized by the skeletal muscle&#xD;
      and may worsen encephalopathy. Alternatively, modifying the source of nitrogen by using more&#xD;
      vegetable protein, less animal protein, and/or branched-chain aminoacids (BCAA)&#xD;
      supplementation may help prevent encephalopathy, sarcopenia and adipopenia. Yet, a recently&#xD;
      published Cochrane review showed that BCAA did have a beneficial effect on hepatic&#xD;
      encephalopathy, but found no effect on mortality, quality of life, or nutritional parameters.&#xD;
      This absence of benefit in nutritional parameters might be counter intuitive, as BCAA provide&#xD;
      a source of energy to the muscle in addition to being substrates for protein synthesis. The&#xD;
      investigators hypothesize that beneficial effects associated to BCAA are, at least partially,&#xD;
      mediated by some product/s of their metabolism, likely formed by hepatic synthesis. The&#xD;
      cirrhosis-associated liver damage would be hence impeding their synthesis. As consequence, to&#xD;
      obtain the expected beneficial outcomes of the BCAA ingestion there should be an increase of&#xD;
      the supplemented BCAA or a direct supplementation of the active metabolite/s.&#xD;
&#xD;
      b. Objectives HMB is produced from leucine and is one of its most active metabolites. The&#xD;
      majority of HMB production occurs in the liver. Since the mid-1990s, a large body of studies&#xD;
      have described that HMB is safe and effective in preventing muscle loss during chronic&#xD;
      diseases. Moreover, recent studies have also indicated effects of HMB itself or its parent&#xD;
      metabolite, leucine, on adipose tissue differentiation, glucose intolerance, inflammation,&#xD;
      gut microbiota, and inflammation reduction. All these beneficial properties make HMB an ideal&#xD;
      candidate to supplement the diet of individuals with cirrhosis, a hypothesis that will be&#xD;
      tested in the current study. Thus, the specific aim of this proposal is to perform a&#xD;
      randomized clinical trial to evaluate the efficacy of HMB, administered as nutritional&#xD;
      supplementation, on clinical symptoms of cirrhosis. The study will be performed in adult&#xD;
      individuals with cirrhosis. Power analyses based on previously described variations in muscle&#xD;
      mass were calculated using R software. The required sample size per group for a power level&#xD;
      of 0.9 is estimated to be n = 30,&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 15, 2017</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">March 31, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in body composition</measure>
    <time_frame>Baseline, 6 wk, and final (12 wk)</time_frame>
    <description>changes in body composition, in particular in fat and muscle, will be assessed by bioelectrical impedance analysis (BIA)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Liver Status I</measure>
    <time_frame>Baseline, 6 wk, and final (12 wk)</time_frame>
    <description>Child-Pugh Score</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Liver Status II</measure>
    <time_frame>Baseline, 6 wk, and final (12 wk)</time_frame>
    <description>Liver transaminase enzymes: gamma glutamyl transpeptidase (GGT), aspartate transaminase (AST), and alanine transaminase (ALT) will be combined in a liver functionality score</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Nutritional Status I</measure>
    <time_frame>Baseline, 6 wk, and final (12 wk)</time_frame>
    <description>plasma HMB</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nutritional Status II</measure>
    <time_frame>Baseline, 6 wk, and final (12 wk)</time_frame>
    <description>Plasma lipids: total cholesterol, triglycerides, LDL&amp;HDL-cholesterol, free fatty acids</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nutritional Status III</measure>
    <time_frame>Baseline, 6 wk, and final (12 wk)</time_frame>
    <description>Plasma glucose and insulin will be combined to calculate the homeostatic model assessment (HOMA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammation</measure>
    <time_frame>Baseline, 6 wk, and final (12 wk)</time_frame>
    <description>C reactive protein</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">43</enrollment>
  <condition>Sarcopenia</condition>
  <condition>Cirrhosis</condition>
  <condition>Malnutrition</condition>
  <arm_group>
    <arm_group_label>HMB</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HMB Group (n=30) will receive received twice a day for 3 months a specialized, nutrient-dense ready-to-drink liquid (Abbott Nutrition) with 350 kcal, 20 g protein, 11 g fat, 44 g carbohydrate, 1.5 g calcium-HMB, 160 IU vitamin D and other essential micronutrients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Control Group (n=30) will receive twice a day for 3 months another supplement with similar composition in macro- and micro-nutrients but without HMB</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Ensure Plus Advance</intervention_name>
    <description>Supplements, labeled only with the name of the participant and his/her identification number, will be provided to the participants in the Translational Research Unit of the Miguel Servet Hospital. Every 2 weeks, changes in body composition, in particular in fat and muscle, will be assessed by bioelectrical impedance analysis (BIA). Likewise they will be asked about compliance and their diets will be controlled by a nutritionist. Fresh stool samples, urine and blood will be collected pre- and post treatment. An extensive bloodwork will be performed at the Clinical Biochemistry Service at the Miguel Servet Hospital (plasma HMB, total cholesterol, triglycerides, LDL&amp;HDL-cholesterol, free fatty acids, glucose, insulin, β-hydroxybutyrate, hs-CRP, and liver transaminases (AST, ALT, GGT).</description>
    <arm_group_label>HMB</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Ensure High Protein</intervention_name>
    <description>Supplements, labeled only with the name of the participant and his/her identification number, will be provided to the participants in the Translational Research Unit of the Miguel Servet Hospital. Every 2 weeks, changes in body composition, in particular in fat and muscle, will be assessed by bioelectrical impedance analysis (BIA). Likewise they will be asked about compliance and their diets will be controlled by a nutritionist. Fresh stool samples, urine and blood will be collected pre- and post treatment. An extensive bloodwork will be performed at the Clinical Biochemistry Service at the Miguel Servet Hospital (plasma HMB, total cholesterol, triglycerides, LDL&amp;HDL-cholesterol, free fatty acids, glucose, insulin, β-hydroxybutyrate, hs-CRP, and liver transaminases (AST, ALT, GGT).</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. negative for hepatitis C virus (HCV)&amp;hepatitis B virus (HBV) , or alcohol-caused&#xD;
             cirrhosis in stable clinical condition,&#xD;
&#xD;
          2. alcoholic patients must have been abstinent for at least 6 months and be in Child's&#xD;
             score of ≤7,&#xD;
&#xD;
          3. no gastrointestinal bleeding for at least 3 months,&#xD;
&#xD;
          4. no clinical, microbiological, or laboratory evidence of infection, renal failure,&#xD;
             encephalopathy, malignancy, diabetes mellitus, comorbidities including heart failure&#xD;
             or pulmonary disease,&#xD;
&#xD;
          5. No use of medications that affect protein turnover, including corticosteroids and&#xD;
             β-blockers.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alejandro Sanz-Paris, MD</last_name>
    <role>Study Director</role>
    <affiliation>Hospital Miguel Servet</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Universitario Miguel Servet</name>
      <address>
        <city>Zaragoza</city>
        <zip>50009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <reference>
    <citation>Petrides AS, DeFronzo RA. Glucose and insulin metabolism in cirrhosis. J Hepatol. 1989 Jan;8(1):107-14. doi: 10.1016/0168-8278(89)90169-4.</citation>
    <PMID>2646365</PMID>
  </reference>
  <reference>
    <citation>Montano-Loza AJ, Meza-Junco J, Prado CM, Lieffers JR, Baracos VE, Bain VG, Sawyer MB. Muscle wasting is associated with mortality in patients with cirrhosis. Clin Gastroenterol Hepatol. 2012 Feb;10(2):166-73, 173.e1. doi: 10.1016/j.cgh.2011.08.028. Epub 2011 Sep 3.</citation>
    <PMID>21893129</PMID>
  </reference>
  <reference>
    <citation>Qiu J, Thapaliya S, Runkana A, Yang Y, Tsien C, Mohan ML, Narayanan A, Eghtesad B, Mozdziak PE, McDonald C, Stark GR, Welle S, Naga Prasad SV, Dasarathy S. Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-kappaB-mediated mechanism. Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18162-7. doi: 10.1073/pnas.1317049110. Epub 2013 Oct 21.</citation>
    <PMID>24145431</PMID>
  </reference>
  <reference>
    <citation>Floreani A, Variola A, Niro G, Premoli A, Baldo V, Gambino R, Musso G, Cassader M, Bo S, Ferrara F, Caroli D, Rizzotto ER, Durazzo M. Plasma adiponectin levels in primary biliary cirrhosis: a novel perspective for link between hypercholesterolemia and protection against atherosclerosis. Am J Gastroenterol. 2008 Aug;103(8):1959-65. doi: 10.1111/j.1572-0241.2008.01888.x. Epub 2008 Jun 28.</citation>
    <PMID>18564121</PMID>
  </reference>
  <reference>
    <citation>Tilg H, Kaser A, Moschen AR. How to modulate inflammatory cytokines in liver diseases. Liver Int. 2006 Nov;26(9):1029-39. doi: 10.1111/j.1478-3231.2006.01339.x.</citation>
    <PMID>17032402</PMID>
  </reference>
  <reference>
    <citation>Lin SY, Sheu WH, Chen WY, Lee FY, Huang CJ. Stimulated resistin expression in white adipose of rats with bile duct ligation-induced liver cirrhosis: relationship to cirrhotic hyperinsulinemia and increased tumor necrosis factor-alpha. Mol Cell Endocrinol. 2005 Mar 31;232(1-2):1-8. doi: 10.1016/j.mce.2005.01.006.</citation>
    <PMID>15737463</PMID>
  </reference>
  <reference>
    <citation>Betrapally NS, Gillevet PM, Bajaj JS. Gut microbiome and liver disease. Transl Res. 2017 Jan;179:49-59. doi: 10.1016/j.trsl.2016.07.005. Epub 2016 Jul 15.</citation>
    <PMID>27477080</PMID>
  </reference>
  <reference>
    <citation>Plauth M, Cabre E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J; DGEM (German Society for Nutritional Medicine); Ferenci P, Holm E, Vom Dahl S, Muller MJ, Nolte W; ESPEN (European Society for Parenteral and Enteral Nutrition). ESPEN Guidelines on Enteral Nutrition: Liver disease. Clin Nutr. 2006 Apr;25(2):285-94. doi: 10.1016/j.clnu.2006.01.018. Epub 2006 May 16.</citation>
    <PMID>16707194</PMID>
  </reference>
  <reference>
    <citation>Plauth M, Cabre E, Campillo B, Kondrup J, Marchesini G, Schutz T, Shenkin A, Wendon J; ESPEN. ESPEN Guidelines on Parenteral Nutrition: hepatology. Clin Nutr. 2009 Aug;28(4):436-44. doi: 10.1016/j.clnu.2009.04.019. Epub 2009 Jun 11.</citation>
    <PMID>19520466</PMID>
  </reference>
  <reference>
    <citation>Ney M, Vandermeer B, van Zanten SJ, Ma MM, Gramlich L, Tandon P. Meta-analysis: oral or enteral nutritional supplementation in cirrhosis. Aliment Pharmacol Ther. 2013 Apr;37(7):672-9. doi: 10.1111/apt.12252. Epub 2013 Feb 20.</citation>
    <PMID>23421379</PMID>
  </reference>
  <reference>
    <citation>Koretz RL, Avenell A, Lipman TO. Nutritional support for liver disease. Cochrane Database Syst Rev. 2012 May 16;2012(5):CD008344. doi: 10.1002/14651858.CD008344.pub2.</citation>
    <PMID>22592729</PMID>
  </reference>
  <reference>
    <citation>Dasarathy S, Merli M. Sarcopenia from mechanism to diagnosis and treatment in liver disease. J Hepatol. 2016 Dec;65(6):1232-1244. doi: 10.1016/j.jhep.2016.07.040. Epub 2016 Aug 8.</citation>
    <PMID>27515775</PMID>
  </reference>
  <reference>
    <citation>Nguyen DL, Morgan T. Protein restriction in hepatic encephalopathy is appropriate for selected patients: a point of view. Hepatol Int. 2014 Sep 1;8(2):447-51. doi: 10.1007/s12072-013-9497-1.</citation>
    <PMID>25525477</PMID>
  </reference>
  <reference>
    <citation>Gluud LL, Dam G, Les I, Marchesini G, Borre M, Aagaard NK, Vilstrup H. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017 May 18;5(5):CD001939. doi: 10.1002/14651858.CD001939.pub4.</citation>
    <PMID>28518283</PMID>
  </reference>
  <reference>
    <citation>Krebs HA, Lund P. Aspects of the regulation of the metabolism of branched-chain amino acids. Adv Enzyme Regul. 1976;15:375-94. doi: 10.1016/0065-2571(77)90026-7. No abstract available.</citation>
    <PMID>19935</PMID>
  </reference>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>September 11, 2017</study_first_submitted>
  <study_first_submitted_qc>September 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 15, 2017</study_first_posted>
  <last_update_submitted>May 1, 2021</last_update_submitted>
  <last_update_submitted_qc>May 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Instituto Aragones de Ciencias de la Salud</investigator_affiliation>
    <investigator_full_name>Jose Miguel Arbones Mainar</investigator_full_name>
    <investigator_title>Senior Researcher</investigator_title>
  </responsible_party>
  <keyword>HMB</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Cirrhosis</mesh_term>
    <mesh_term>Sarcopenia</mesh_term>
    <mesh_term>Malnutrition</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03285217
org study id: HEPATIC
nct id: NCT03285217
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Cirrhosis is a late stage of hepatic fibrosis caused by many forms of liver diseases and
      conditions, such as hepatitis and chronic alcoholism. The World Health Organization (WHO) has
      reported that this condition accounts for 1.8% of all deaths in Europe (170,000 deaths/year).

      Patients with cirrhosis are characterized by severe metabolic alterations, which converge in
      a malnutritional state. Malnutrition encompasses glucose intolerance, chronic inflammation,
      altered gut microbiota, reduced muscle mass (sarcopenia), as well as loss and dysregulation
      of adipose tissue (adipopenia). Malnutrition is the most frequent complication that adversely
      affects the outcomes of cirrhotic patients. Yet, despite its clinical repercussions and
      potential reversibility, there are no effective therapies because our limited understanding
      of the mechanisms underlying this altered metabolism.

      β-hydroxy β-methylbutyrate (HMB) is a naturally produced substance regarded as safe and
      effective in preventing muscle loss during chronic diseases. Previous studies have indicated
      some beneficial effects of HMB itself or its parent metabolite, leucine, on adipose tissue,
      glucose intolerance, inflammation, and gut microbiota. This study aims to translate those
      beneficial effects to cirrhotic patients. The investigators hypothesize that HMB can improve
      cirrhosis-related metabolic abnormalities through its pleiotropic effects. The goals of this
      study are: i) to perform a randomized clinical trial to evaluate the efficacy of HMB,
      administered as nutritional supplementation, on clinical symptoms of cirrhosis.

      ii) to uncover the precise metabolic pathways that underlie HMB action, with a special focus
      on muscle, adipose tissue, and gut microbiota.
1. Scientific & technical aspects

      State of the art:

      Patients with cirrhosis present a chronic inflammatory state and alterations in protein
      metabolism. These alterations lead to elevated levels of insulin and catecholamines along
      with the development of glucose intolerance and insulin resistance. The reduced availability
      of glucose as energy source translates into an accelerated starvation with reduced body fat
      mass (adipopenia) and loss of skeletal muscle mass (sarcopenia). This catabolic state reduces
      survival and post-liver transplant outcomes in patients with cirrhosis.

      Loss of skeletal muscle mass or sarcopenia is the major component of malnutrition in
      cirrhosis and occurs in the majority of patients. Impaired ureagenesis and portosystemic
      shunting provoke skeletal muscle hyperammonemia which induces up-regulation of myostatin and
      increased autophagy, both of which contribute to sarcopenia.

      The adipose tissue (AT) regulates energy homeostasis in the body regardless of the obesity
      status. Indeed, serum levels of the main adipose-produced cytokines (adipokines) such as
      leptin, adiponectin, and resistin have been found to be increased in cirrhotic patients as
      liver function worsens. Evidence demonstrated that adiponectin interacts with the
      immune/macrophage system and might be of relevance in many liver diseases. Likewise,
      hyperinsulinemia and increased tumor necrosis factor (TNF) α levels upregulated the adipose
      resistin gene in rat models of liver cirrhosis.

      Recently, growing attention has been targeted to the gut microbiota (GM) in the pathogenesis
      of gastrointestinal diseases. GM constitutes a symbiotic ecosystem that keeps homeostatic
      balance within the human body producing a diverse range of compounds that have a major role
      in regulating the activity of distal organs. Recent studies have shown changes in the
      relative abundance of microbiota in the stool, colonic mucosa, and saliva of cirrhotic
      patients. Therefore, modulation of GM arises as a promising tool to prevent and/or to treat
      the development of these liver disorders.

      Clinical guidelines recommend to provide adequate amounts of calories and proteins to
      cirrhotic patients, either by frequent feeding or via diet supplementation. Consequently,
      different high caloric diets have been extensively studied. Yet, few studies have shown
      significant benefit of this type of diets in malnourished cirrhotic patients. Protein
      supplementation may improve the availability of essential amino acids. However, animal
      proteins are enriched in aromatic amino acids that are not metabolized by the skeletal muscle
      and may worsen encephalopathy. Alternatively, modifying the source of nitrogen by using more
      vegetable protein, less animal protein, and/or branched-chain aminoacids (BCAA)
      supplementation may help prevent encephalopathy, sarcopenia and adipopenia. Yet, a recently
      published Cochrane review showed that BCAA did have a beneficial effect on hepatic
      encephalopathy, but found no effect on mortality, quality of life, or nutritional parameters.
      This absence of benefit in nutritional parameters might be counter intuitive, as BCAA provide
      a source of energy to the muscle in addition to being substrates for protein synthesis. The
      investigators hypothesize that beneficial effects associated to BCAA are, at least partially,
      mediated by some product/s of their metabolism, likely formed by hepatic synthesis. The
      cirrhosis-associated liver damage would be hence impeding their synthesis. As consequence, to
      obtain the expected beneficial outcomes of the BCAA ingestion there should be an increase of
      the supplemented BCAA or a direct supplementation of the active metabolite/s.

      b. Objectives HMB is produced from leucine and is one of its most active metabolites. The
      majority of HMB production occurs in the liver. Since the mid-1990s, a large body of studies
      have described that HMB is safe and effective in preventing muscle loss during chronic
      diseases. Moreover, recent studies have also indicated effects of HMB itself or its parent
      metabolite, leucine, on adipose tissue differentiation, glucose intolerance, inflammation,
      gut microbiota, and inflammation reduction. All these beneficial properties make HMB an ideal
      candidate to supplement the diet of individuals with cirrhosis, a hypothesis that will be
      tested in the current study. Thus, the specific aim of this proposal is to perform a
      randomized clinical trial to evaluate the efficacy of HMB, administered as nutritional
      supplementation, on clinical symptoms of cirrhosis. The study will be performed in adult
      individuals with cirrhosis. Power analyses based on previously described variations in muscle
      mass were calculated using R software. The required sample size per group for a power level
      of 0.9 is estimated to be n = 30,
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Changes in body composition
time frame: Baseline, 6 wk, and final (12 wk)
description: changes in body composition, in particular in fat and muscle, will be assessed by bioelectrical impedance analysis (BIA)
measure: Liver Status I
time frame: Baseline, 6 wk, and final (12 wk)
description: Child-Pugh Score
measure: Liver Status II
time frame: Baseline, 6 wk, and final (12 wk)
description: Liver transaminase enzymes: gamma glutamyl transpeptidase (GGT), aspartate transaminase (AST), and alanine transaminase (ALT) will be combined in a liver functionality score
measure: Nutritional Status I
time frame: Baseline, 6 wk, and final (12 wk)
description: plasma HMB
measure: Nutritional Status II
time frame: Baseline, 6 wk, and final (12 wk)
description: Plasma lipids: total cholesterol, triglycerides, LDL&HDL-cholesterol, free fatty acids
measure: Nutritional Status III
time frame: Baseline, 6 wk, and final (12 wk)
description: Plasma glucose and insulin will be combined to calculate the homeostatic model assessment (HOMA)
measure: Inflammation
time frame: Baseline, 6 wk, and final (12 wk)
description: C reactive protein
arm group label: HMB
arm group type: Experimental
description: HMB Group (n=30) will receive received twice a day for 3 months a specialized, nutrient-dense ready-to-drink liquid (Abbott Nutrition) with 350 kcal, 20 g protein, 11 g fat, 44 g carbohydrate, 1.5 g calcium-HMB, 160 IU vitamin D and other essential micronutrients.
arm group label: Control
arm group type: Active Comparator
description: Control Group (n=30) will receive twice a day for 3 months another supplement with similar composition in macro- and micro-nutrients but without HMB
intervention type: Dietary Supplement
intervention name: Ensure Plus Advance
description: Supplements, labeled only with the name of the participant and his/her identification number, will be provided to the participants in the Translational Research Unit of the Miguel Servet Hospital. Every 2 weeks, changes in body composition, in particular in fat and muscle, will be assessed by bioelectrical impedance analysis (BIA). Likewise they will be asked about compliance and their diets will be controlled by a nutritionist. Fresh stool samples, urine and blood will be collected pre- and post treatment. An extensive bloodwork will be performed at the Clinical Biochemistry Service at the Miguel Servet Hospital (plasma HMB, total cholesterol, triglycerides, LDL&HDL-cholesterol, free fatty acids, glucose, insulin, β-hydroxybutyrate, hs-CRP, and liver transaminases (AST, ALT, GGT).
arm group label: HMB
intervention type: Dietary Supplement
intervention name: Ensure High Protein
description: Supplements, labeled only with the name of the participant and his/her identification number, will be provided to the participants in the Translational Research Unit of the Miguel Servet Hospital. Every 2 weeks, changes in body composition, in particular in fat and muscle, will be assessed by bioelectrical impedance analysis (BIA). Likewise they will be asked about compliance and their diets will be controlled by a nutritionist. Fresh stool samples, urine and blood will be collected pre- and post treatment. An extensive bloodwork will be performed at the Clinical Biochemistry Service at the Miguel Servet Hospital (plasma HMB, total cholesterol, triglycerides, LDL&HDL-cholesterol, free fatty acids, glucose, insulin, β-hydroxybutyrate, hs-CRP, and liver transaminases (AST, ALT, GGT).
arm group label: Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Alejandro Sanz-Paris, MD
role: Study Director
affiliation: Hospital Miguel Servet
facility: 
country: Spain
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responsible party type: Principal Investigator
investigator affiliation: Instituto Aragones de Ciencias de la Salud
investigator full name: Jose Miguel Arbones Mainar
investigator title: Senior Researcher
mesh term: Liver Cirrhosis
mesh term: Sarcopenia
mesh term: Malnutrition
mesh term: Fibrosis
sharing ipd: Undecided