<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/NCT03234920</url>
  </required_header>
  <id_info>
    <org_study_id>URomLSHMB</org_study_id>
    <nct_id>NCT03234920</nct_id>
  </id_info>
  <brief_title>Beta-Hydroxy-Beta-Methylbutyrate (HMB) Supplementation After Liver Transplantation</brief_title>
  <acronym>HMB</acronym>
  <official_title>Effects of Beta-hydroxy-beta-methylbutyrate (HMB) Supplementation After Liver Transplantation: Randomized and Controlled Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Roma La Sapienza</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Roma La Sapienza</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Sarcopenia is an independent predictor of morbidity and mortality in cirrhotic patient before&#xD;
      and after liver transplantation. Beta-hydroxy-beta-methyl butyrate (HMB) is a leucine&#xD;
      metabolite with potential efficacy in increasing protein synthesis, muscle mass and its&#xD;
      functionality.&#xD;
&#xD;
      The aim of this randomized controlled study is to evaluate the effect of a nutritional&#xD;
      supplementation with HMB after liver transplantation both on muscle mass and on muscle&#xD;
      function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Protocol&#xD;
&#xD;
        1. Introduction:&#xD;
&#xD;
           Sarcopenia, a condition of skeletal muscle mass depletion and reduction of muscle&#xD;
           strength, is the most important aspect of malnutrition secondary to liver cirrhosis.&#xD;
           Sarcopenia is recognized to be an independent factor of morbidity and mortality befor&#xD;
           and after liver transplantation. The prevalence of sarcopenia in liver transplanted&#xD;
           patients has been reported to vary between 40% and 76%. Sarcopenia in hepatic cirrhosis&#xD;
           occurs as a result of an increase in proteolysis or a reduction in protein synthesis, or&#xD;
           a combination of the two mechanisms. The alterations in the molecular pathways that&#xD;
           regulate these mechanisms are not entirely known. Recent studies reported an increased&#xD;
           expression of myostatin, a member of the transforming growth factor ß superfamily , in&#xD;
           skeletal muscles of animal models with liver cirrhosis and in plasma of cirrhotic&#xD;
           patients. The authors suggested that the increased expression of myostatin resulted in&#xD;
           protein synthesis inhibition. In addition, myostatin is able to activate AMPK protein&#xD;
           kinase, a signaling inhibitor of mTOR (mammalian target of rapamycin), key regulator of&#xD;
           protein synthesis.&#xD;
&#xD;
           After Liver transplant, secondary to the recovery of liver function, the progressive&#xD;
           increase in caloric intakes and the increase in daily physical activity, an improvement&#xD;
           in the nutritional status of the patient and normalization of body composition is&#xD;
           expected. However, available data on the modification of nutritional status after liver&#xD;
           transplantation do not confirm the expected results: worsening of nutritional status was&#xD;
           reported in the perioperative period with further depletion of lean mass as a result of&#xD;
           surgical stress, bed rest and postoperative complications. A lack of recovery of muscle&#xD;
           mass was documented even after one year of transplantation.&#xD;
&#xD;
           Molecular mechanisms responsible for sarcopenia after liver transplantation are not&#xD;
           fully clarified. The only study on a small sample of muscle biopsies in post-transplant&#xD;
           patients described a persistent increase in myostatin expression in these patients. The&#xD;
           immunosuppressive therapy used in the post transplant involves the use of calcineurin&#xD;
           inhibitors, a protein involved in differentiation and hypertrophy of muscle fibers, mTOR&#xD;
           inhibitors and corticosteroids. The use of these drugs is another factor contributing to&#xD;
           sarcopenia after transplantation.&#xD;
&#xD;
           o HMB: HMB is a metabolite of leucine with the potential to increase performance and&#xD;
           muscle trophism. Studies in experimental models of cachexia have resulted in increased&#xD;
           phosphorylation and activation of secondary mTOR after use of HMB. Experimental studies&#xD;
           performed on myoblastic cell cultures also revealed an increased expression of IGF-1&#xD;
           secondary to HMB treatment. Such evidence confirms the anabolic properties of the HMB.&#xD;
           HMB has also been shown to suppress proteolysis by inhibition of the&#xD;
           ubiquitin-proteasome pathway in models of neoplastic cachexia and to eb effective in&#xD;
           reducing muscular atrophy secondary to steroid therapy. The association of&#xD;
           anti-proteolytic and anabolic properties targeting mTOR make HMB a potentially effective&#xD;
           supplement for the treatment of sarcopenia after liver transplantation. There are&#xD;
           currently no data on the use of HMB in this category of patients.&#xD;
&#xD;
        2. Aims of the study:&#xD;
&#xD;
           Primary aim of the study: Evaluate the therapeutic efficacy of HMB supplementation for&#xD;
           three months in patients undergoing liver transplantation on recovery of skeletal muscle&#xD;
           mass shortly after transplantation (third to fourth month after transplantation).&#xD;
&#xD;
           Secondary aims of the study:&#xD;
&#xD;
             -  Evaluate the therapeutic efficacy of HMB supplementation for three months in&#xD;
                patients undergoing liver transplantation on recovery of skeletal muscular function&#xD;
                shortly after transplantation (third to fourth month after transplantation).&#xD;
&#xD;
             -  Evaluate the long-term effects of HMB supplementation in terms of recovery of&#xD;
                skeletal muscle mass (6 and 12 months after transplantation).&#xD;
&#xD;
             -  Evaluate the possible effect of HMB supplementation on post-transplant morbidity&#xD;
                (hospitalization, infectious complications, onset of metabolic complications).&#xD;
&#xD;
             -  Evaluate tolerance for HMB intake in liver transplant patients&#xD;
&#xD;
           This controlled trial is not sponsored by a drug company.&#xD;
&#xD;
        3. Patients:&#xD;
&#xD;
           The protocol of the study needs to be approved by the local ethic committee. Patients&#xD;
           are enrolled in the study after been informed of the purpose and protocol of treatment&#xD;
           and need to sign a written informed consent.&#xD;
&#xD;
        4. Statistical analysis, sample size and randomization:&#xD;
&#xD;
           For categorical variables, the Person-Chi-square test or the Fischer test will be used.&#xD;
           For continuous variables, the Mann-Whitney Test will be used. The ANOVA variance&#xD;
           analysis will be applied followed by the &quot;t-test&quot; when significant differences will be&#xD;
           highlighted. Values of p &lt;0.05 will be considered statistically significant.&#xD;
&#xD;
           For the sample size calculation, the increase in muscle mass, evaluated by DEXA and&#xD;
           expressed as Fat Free Mass Index-FFMI (core indexed for height), 12 weeks after the&#xD;
           beginning of supplementation was considered as the primary endpoint. On the basis of&#xD;
           literature data, the investigators expect unchanged lean mass in the control group with&#xD;
           a DS of ± 1 kg / m2 at 3-4 months after supplementation. In the HMB-treated group the&#xD;
           investigators expect to increase the FFMI of 1.2 kg / m2 with the same DS. A total of 12&#xD;
           patients per group will need to have a statistical power of at least 80% with an alpha&#xD;
           error of 5%.Block randomization, consisting of 4 individuals per block, was executed in&#xD;
           a 1:1ratio using random numbers generated by an independent statistician (SPSS version&#xD;
           16.0). Knowledge of the randomization code was limited to the physician.&#xD;
&#xD;
        5. Protocol of the study:&#xD;
&#xD;
      Basal Evaluation:&#xD;
&#xD;
      The registration will include the main clinical and biochemical data prior to transplantation&#xD;
      (including nutritional evaluation if present) and after transplantation.&#xD;
&#xD;
      Nutritional counseling will be provided to all patients to ensure similar caloric and daily&#xD;
      protein intake in the two groups, according to the current guidelines (caloric intake of&#xD;
      20-25 kcal / kg / die ± 10%, protein intake of 1.2 g / kg / day).&#xD;
&#xD;
      At the time of the enrollment and during the subsequent controls the following data will be&#xD;
      recorded :&#xD;
&#xD;
        1. calorie intake in the week preceding the visit by a three days non-consecutive food&#xD;
           diary;&#xD;
&#xD;
        2. anthropometric parameters (height, weight, body mass index, brachial circumference,&#xD;
           triceps)&#xD;
&#xD;
        3. body composition by dual-energy-xray-absorptiometry (DEXA) using dedicated software to&#xD;
           estimated fat free mass index (FFMI) (Fat free mass in kg/ height in cm)&#xD;
&#xD;
        4. muscular function evaluated by 6 minute walk test-6MWT, Timed Up and Go test-TUGT), e&#xD;
           l'Hand grip Test (HG).&#xD;
&#xD;
        5. biochemical and metabolic parameters&#xD;
&#xD;
        6. pharmacological therapy&#xD;
&#xD;
      During the study, clinical complications (hospital admissions, infectious events, onset of&#xD;
      comorbidity) will be recorded.&#xD;
&#xD;
      During the study, the tolerability of the supplement (analogue-visual scale), adherence to&#xD;
      absorption and any intolerance or secondary adverse effects will be detected.&#xD;
&#xD;
      Randomization: Patient are randomized to Group 1 - placebo (or control group) and Group 2 -&#xD;
      supplementation (or treatment group)&#xD;
&#xD;
      Randomization: Patient are randomized to Group 1 - placebo (or control group) and Group 2 -&#xD;
      supplementation (or treatment group)&#xD;
&#xD;
      The placebo will be 200 ml of fruit juice given twice daily. Supplementation will be HMB 1.5&#xD;
      g dissolved in 200 ml of fruit juice and taken twice daily. Supplementation/placebo will be&#xD;
      provided for 12 weeks.&#xD;
&#xD;
      End-points of the study:&#xD;
&#xD;
        -  Recovery of FFMI ( 3°-4° after liver transplantation)&#xD;
&#xD;
        -  Recovery of muscle function (amelioration of 6-MWT, TUGT test and HG test) (3-4°, 6° and&#xD;
           12th month after liver transplantation )&#xD;
&#xD;
        -  Reduction of morbidity after liver transplantation (Hospital admission, infections,&#xD;
           onset of metabolic disease) 3-4°, 6° and 12th month after liver transplantation )&#xD;
&#xD;
        -  Tolerably of HMB supplementation ( 3°-4° after liver transplantation) Collateral effects&#xD;
           of HMB are recorded.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 25, 2015</start_date>
  <completion_date type="Actual">September 15, 2018</completion_date>
  <primary_completion_date type="Actual">September 15, 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>
    <intervention_model_description>Parallel Assignment</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in Fat Free Mass Index 3-4 months after transplantation</measure>
    <time_frame>3-4° months after transplantation</time_frame>
    <description>Increase of Fat Free Mass Index-FFMI (FFMI) evaluated by DEXA</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in Fat Free Mass Index 6 and 12 months after transplantation</measure>
    <time_frame>6° and 12° months after transplantation</time_frame>
    <description>Increase of Fat Free Mass Index-FFMI (FFMI) evaluated by DEXA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in 6MWT at 3-4, 6 and 12 months after transplantation</measure>
    <time_frame>3°-4°, 6° and 12° months after transplantation</time_frame>
    <description>Recovery of muscle mass function evaluated by minute walk test-6MWT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in test-TUGT at 3-4, 6 and 12 months after transplantation</measure>
    <time_frame>3°-4°, 6° and 12° months after transplantation</time_frame>
    <description>Recovery of muscle mass function evaluated by Timed Up and Go test-TUGT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in HG Test at 3-4, 6 and 12 months after transplantation</measure>
    <time_frame>3°-4°, 6° and 12° months after transplantation</time_frame>
    <description>Recovery of muscle mass function evaluated by Recovery of muscle mass function evaluated by Hand grip Test (HG)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of days of hospitalization during the study period</measure>
    <time_frame>3°-4°, 6° and 12° months after transplantation</time_frame>
    <description>Days of Hospitalization will be recorded</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of onset of metabolic syndrome after liver transplantation classified sec. APT III classification</measure>
    <time_frame>3°-4°, 6° and 12° months after transplantation</time_frame>
    <description>onset of metabolic syndrome diagnosed by ATP III classification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events evaluated to analog-visual scale</measure>
    <time_frame>3°-4°, 6° and 12° months after transplantation</time_frame>
    <description>Tolerability of supplementation evaluated to analog-visual scale</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Sarcopenia</condition>
  <arm_group>
    <arm_group_label>Group 1- Control Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo The placebo will be 200 ml of fruit juice twice a day. Placebo will be provided for 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2 - Treatment group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HMB Supplementation with 1.5 g of HMB dissolved in 200 ml of fruit juice and taken twice daily. Supplementation will be provided for 12 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>BETA-HYDROXY-BETA-METHYLBUTYRATE (HMB)</intervention_name>
    <description>1.5 g of HMB dissolved in 200 ml of fruit juice will be provided for 12 weeks twice daily</description>
    <arm_group_label>Group 2 - Treatment group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>The placebo will be 200 ml of fruit juice given twice daily</description>
    <arm_group_label>Group 1- Control Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1. Liver transplantation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. Multiple organ transplantation&#xD;
&#xD;
          -  2. Low compliance&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Manuela Merli, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Roma La Sapienza</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Gastroenterology Department, Sapienza University of Rome</name>
      <address>
        <city>Rome</city>
        <zip>00100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Dasarathy S. Consilience in sarcopenia of cirrhosis. J Cachexia Sarcopenia Muscle. 2012 Dec;3(4):225-37. doi: 10.1007/s13539-012-0069-3. Epub 2012 May 31.</citation>
    <PMID>22648736</PMID>
  </reference>
  <reference>
    <citation>Merli M, Giusto M, Riggio O, et al. Improvement of nutritional status in malnourished cirrhotic patients one year after liver transplantation. eESPEN 2011 (2011) e1-e6</citation>
  </reference>
  <reference>
    <citation>Giusto M, Lattanzi B, Albanese C, Galtieri A, Farcomeni A, Giannelli V, Lucidi C, Di Martino M, Catalano C, Merli M. Sarcopenia in liver cirrhosis: the role of computed tomography scan for the assessment of muscle mass compared with dual-energy X-ray absorptiometry and anthropometry. Eur J Gastroenterol Hepatol. 2015 Mar;27(3):328-34. doi: 10.1097/MEG.0000000000000274.</citation>
    <PMID>25569567</PMID>
  </reference>
  <reference>
    <citation>Tsien C, Garber A, Narayanan A, Shah SN, Barnes D, Eghtesad B, Fung J, McCullough AJ, Dasarathy S. Post-liver transplantation sarcopenia in cirrhosis: a prospective evaluation. J Gastroenterol Hepatol. 2014 Jun;29(6):1250-7. doi: 10.1111/jgh.12524.</citation>
    <PMID>24443785</PMID>
  </reference>
  <reference>
    <citation>Aversa Z, Bonetto A, Costelli P, Minero VG, Penna F, Baccino FM, Lucia S, Rossi Fanelli F, Muscaritoli M. beta-hydroxy-beta-methylbutyrate (HMB) attenuates muscle and body weight loss in experimental cancer cachexia. Int J Oncol. 2011 Mar;38(3):713-20. doi: 10.3892/ijo.2010.885. Epub 2010 Dec 23.</citation>
    <PMID>21184031</PMID>
  </reference>
  <reference>
    <citation>Gerlinger-Romero F, Guimaraes-Ferreira L, Giannocco G, Nunes MT. Chronic supplementation of beta-hydroxy-beta methylbutyrate (HMbeta) increases the activity of the GH/IGF-I axis and induces hyperinsulinemia in rats. Growth Horm IGF Res. 2011 Apr;21(2):57-62. doi: 10.1016/j.ghir.2010.12.006. Epub 2011 Jan 14.</citation>
    <PMID>21237681</PMID>
  </reference>
  <reference>
    <citation>Aversa Z, Alamdari N, Castillero E, Muscaritoli M, Rossi Fanelli F, Hasselgren PO. beta-Hydroxy-beta-methylbutyrate (HMB) prevents dexamethasone-induced myotube atrophy. Biochem Biophys Res Commun. 2012 Jul 13;423(4):739-43. doi: 10.1016/j.bbrc.2012.06.029. Epub 2012 Jun 13.</citation>
    <PMID>22705301</PMID>
  </reference>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>July 17, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <last_update_submitted>March 8, 2019</last_update_submitted>
  <last_update_submitted_qc>March 8, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">March 11, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Roma La Sapienza</investigator_affiliation>
    <investigator_full_name>Manuela Merli</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>cirrhosis</keyword>
  <keyword>liver transplantation</keyword>
  <keyword>HMB</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sarcopenia</mesh_term>
  </condition_browse>
  <!-- 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/NCT03234920
org study id: URomLSHMB
nct id: NCT03234920
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Sarcopenia is an independent predictor of morbidity and mortality in cirrhotic patient before
      and after liver transplantation. Beta-hydroxy-beta-methyl butyrate (HMB) is a leucine
      metabolite with potential efficacy in increasing protein synthesis, muscle mass and its
      functionality.

      The aim of this randomized controlled study is to evaluate the effect of a nutritional
      supplementation with HMB after liver transplantation both on muscle mass and on muscle
      function.
Protocol

        1. Introduction:

           Sarcopenia, a condition of skeletal muscle mass depletion and reduction of muscle
           strength, is the most important aspect of malnutrition secondary to liver cirrhosis.
           Sarcopenia is recognized to be an independent factor of morbidity and mortality befor
           and after liver transplantation. The prevalence of sarcopenia in liver transplanted
           patients has been reported to vary between 40% and 76%. Sarcopenia in hepatic cirrhosis
           occurs as a result of an increase in proteolysis or a reduction in protein synthesis, or
           a combination of the two mechanisms. The alterations in the molecular pathways that
           regulate these mechanisms are not entirely known. Recent studies reported an increased
           expression of myostatin, a member of the transforming growth factor ß superfamily , in
           skeletal muscles of animal models with liver cirrhosis and in plasma of cirrhotic
           patients. The authors suggested that the increased expression of myostatin resulted in
           protein synthesis inhibition. In addition, myostatin is able to activate AMPK protein
           kinase, a signaling inhibitor of mTOR (mammalian target of rapamycin), key regulator of
           protein synthesis.

           After Liver transplant, secondary to the recovery of liver function, the progressive
           increase in caloric intakes and the increase in daily physical activity, an improvement
           in the nutritional status of the patient and normalization of body composition is
           expected. However, available data on the modification of nutritional status after liver
           transplantation do not confirm the expected results: worsening of nutritional status was
           reported in the perioperative period with further depletion of lean mass as a result of
           surgical stress, bed rest and postoperative complications. A lack of recovery of muscle
           mass was documented even after one year of transplantation.

           Molecular mechanisms responsible for sarcopenia after liver transplantation are not
           fully clarified. The only study on a small sample of muscle biopsies in post-transplant
           patients described a persistent increase in myostatin expression in these patients. The
           immunosuppressive therapy used in the post transplant involves the use of calcineurin
           inhibitors, a protein involved in differentiation and hypertrophy of muscle fibers, mTOR
           inhibitors and corticosteroids. The use of these drugs is another factor contributing to
           sarcopenia after transplantation.

           o HMB: HMB is a metabolite of leucine with the potential to increase performance and
           muscle trophism. Studies in experimental models of cachexia have resulted in increased
           phosphorylation and activation of secondary mTOR after use of HMB. Experimental studies
           performed on myoblastic cell cultures also revealed an increased expression of IGF-1
           secondary to HMB treatment. Such evidence confirms the anabolic properties of the HMB.
           HMB has also been shown to suppress proteolysis by inhibition of the
           ubiquitin-proteasome pathway in models of neoplastic cachexia and to eb effective in
           reducing muscular atrophy secondary to steroid therapy. The association of
           anti-proteolytic and anabolic properties targeting mTOR make HMB a potentially effective
           supplement for the treatment of sarcopenia after liver transplantation. There are
           currently no data on the use of HMB in this category of patients.

        2. Aims of the study:

           Primary aim of the study: Evaluate the therapeutic efficacy of HMB supplementation for
           three months in patients undergoing liver transplantation on recovery of skeletal muscle
           mass shortly after transplantation (third to fourth month after transplantation).

           Secondary aims of the study:

             -  Evaluate the therapeutic efficacy of HMB supplementation for three months in
                patients undergoing liver transplantation on recovery of skeletal muscular function
                shortly after transplantation (third to fourth month after transplantation).

             -  Evaluate the long-term effects of HMB supplementation in terms of recovery of
                skeletal muscle mass (6 and 12 months after transplantation).

             -  Evaluate the possible effect of HMB supplementation on post-transplant morbidity
                (hospitalization, infectious complications, onset of metabolic complications).

             -  Evaluate tolerance for HMB intake in liver transplant patients

           This controlled trial is not sponsored by a drug company.

        3. Patients:

           The protocol of the study needs to be approved by the local ethic committee. Patients
           are enrolled in the study after been informed of the purpose and protocol of treatment
           and need to sign a written informed consent.

        4. Statistical analysis, sample size and randomization:

           For categorical variables, the Person-Chi-square test or the Fischer test will be used.
           For continuous variables, the Mann-Whitney Test will be used. The ANOVA variance
           analysis will be applied followed by the "t-test" when significant differences will be
           highlighted. Values of p <0.05 will be considered statistically significant.

           For the sample size calculation, the increase in muscle mass, evaluated by DEXA and
           expressed as Fat Free Mass Index-FFMI (core indexed for height), 12 weeks after the
           beginning of supplementation was considered as the primary endpoint. On the basis of
           literature data, the investigators expect unchanged lean mass in the control group with
           a DS of ± 1 kg / m2 at 3-4 months after supplementation. In the HMB-treated group the
           investigators expect to increase the FFMI of 1.2 kg / m2 with the same DS. A total of 12
           patients per group will need to have a statistical power of at least 80% with an alpha
           error of 5%.Block randomization, consisting of 4 individuals per block, was executed in
           a 1:1ratio using random numbers generated by an independent statistician (SPSS version
           16.0). Knowledge of the randomization code was limited to the physician.

        5. Protocol of the study:

      Basal Evaluation:

      The registration will include the main clinical and biochemical data prior to transplantation
      (including nutritional evaluation if present) and after transplantation.

      Nutritional counseling will be provided to all patients to ensure similar caloric and daily
      protein intake in the two groups, according to the current guidelines (caloric intake of
      20-25 kcal / kg / die ± 10%, protein intake of 1.2 g / kg / day).

      At the time of the enrollment and during the subsequent controls the following data will be
      recorded :

        1. calorie intake in the week preceding the visit by a three days non-consecutive food
           diary;

        2. anthropometric parameters (height, weight, body mass index, brachial circumference,
           triceps)

        3. body composition by dual-energy-xray-absorptiometry (DEXA) using dedicated software to
           estimated fat free mass index (FFMI) (Fat free mass in kg/ height in cm)

        4. muscular function evaluated by 6 minute walk test-6MWT, Timed Up and Go test-TUGT), e
           l'Hand grip Test (HG).

        5. biochemical and metabolic parameters

        6. pharmacological therapy

      During the study, clinical complications (hospital admissions, infectious events, onset of
      comorbidity) will be recorded.

      During the study, the tolerability of the supplement (analogue-visual scale), adherence to
      absorption and any intolerance or secondary adverse effects will be detected.

      Randomization: Patient are randomized to Group 1 - placebo (or control group) and Group 2 -
      supplementation (or treatment group)

      Randomization: Patient are randomized to Group 1 - placebo (or control group) and Group 2 -
      supplementation (or treatment group)

      The placebo will be 200 ml of fruit juice given twice daily. Supplementation will be HMB 1.5
      g dissolved in 200 ml of fruit juice and taken twice daily. Supplementation/placebo will be
      provided for 12 weeks.

      End-points of the study:

        -  Recovery of FFMI ( 3°-4° after liver transplantation)

        -  Recovery of muscle function (amelioration of 6-MWT, TUGT test and HG test) (3-4°, 6° and
           12th month after liver transplantation )

        -  Reduction of morbidity after liver transplantation (Hospital admission, infections,
           onset of metabolic disease) 3-4°, 6° and 12th month after liver transplantation )

        -  Tolerably of HMB supplementation ( 3°-4° after liver transplantation) Collateral effects
           of HMB are recorded.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Changes in Fat Free Mass Index 3-4 months after transplantation
time frame: 3-4° months after transplantation
description: Increase of Fat Free Mass Index-FFMI (FFMI) evaluated by DEXA
measure: Changes in Fat Free Mass Index 6 and 12 months after transplantation
time frame: 6° and 12° months after transplantation
description: Increase of Fat Free Mass Index-FFMI (FFMI) evaluated by DEXA
measure: Changes in 6MWT at 3-4, 6 and 12 months after transplantation
time frame: 3°-4°, 6° and 12° months after transplantation
description: Recovery of muscle mass function evaluated by minute walk test-6MWT
measure: Changes in test-TUGT at 3-4, 6 and 12 months after transplantation
time frame: 3°-4°, 6° and 12° months after transplantation
description: Recovery of muscle mass function evaluated by Timed Up and Go test-TUGT
measure: Changes in HG Test at 3-4, 6 and 12 months after transplantation
time frame: 3°-4°, 6° and 12° months after transplantation
description: Recovery of muscle mass function evaluated by Recovery of muscle mass function evaluated by Hand grip Test (HG)
measure: Evaluation of days of hospitalization during the study period
time frame: 3°-4°, 6° and 12° months after transplantation
description: Days of Hospitalization will be recorded
measure: Evaluation of onset of metabolic syndrome after liver transplantation classified sec. APT III classification
time frame: 3°-4°, 6° and 12° months after transplantation
description: onset of metabolic syndrome diagnosed by ATP III classification
measure: Incidence of Treatment-Emergent Adverse Events evaluated to analog-visual scale
time frame: 3°-4°, 6° and 12° months after transplantation
description: Tolerability of supplementation evaluated to analog-visual scale
arm group label: Group 1- Control Group
arm group type: Placebo Comparator
description: Placebo The placebo will be 200 ml of fruit juice twice a day. Placebo will be provided for 12 weeks
arm group label: Group 2 - Treatment group
arm group type: Experimental
description: HMB Supplementation with 1.5 g of HMB dissolved in 200 ml of fruit juice and taken twice daily. Supplementation will be provided for 12 weeks
intervention type: Dietary Supplement
intervention name: BETA-HYDROXY-BETA-METHYLBUTYRATE (HMB)
description: 1.5 g of HMB dissolved in 200 ml of fruit juice will be provided for 12 weeks twice daily
arm group label: Group 2 - Treatment group
intervention type: Other
intervention name: Placebo
description: The placebo will be 200 ml of fruit juice given twice daily
arm group label: Group 1- Control Group
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Manuela Merli, Prof
role: Principal Investigator
affiliation: University of Roma La Sapienza
facility: 
country: Italy
citation: Dasarathy S. Consilience in sarcopenia of cirrhosis. J Cachexia Sarcopenia Muscle. 2012 Dec;3(4):225-37. doi: 10.1007/s13539-012-0069-3. Epub 2012 May 31.
PMID: 22648736
citation: Merli M, Giusto M, Riggio O, et al. Improvement of nutritional status in malnourished cirrhotic patients one year after liver transplantation. eESPEN 2011 (2011) e1-e6
citation: Giusto M, Lattanzi B, Albanese C, Galtieri A, Farcomeni A, Giannelli V, Lucidi C, Di Martino M, Catalano C, Merli M. Sarcopenia in liver cirrhosis: the role of computed tomography scan for the assessment of muscle mass compared with dual-energy X-ray absorptiometry and anthropometry. Eur J Gastroenterol Hepatol. 2015 Mar;27(3):328-34. doi: 10.1097/MEG.0000000000000274.
PMID: 25569567
citation: Tsien C, Garber A, Narayanan A, Shah SN, Barnes D, Eghtesad B, Fung J, McCullough AJ, Dasarathy S. Post-liver transplantation sarcopenia in cirrhosis: a prospective evaluation. J Gastroenterol Hepatol. 2014 Jun;29(6):1250-7. doi: 10.1111/jgh.12524.
PMID: 24443785
citation: Aversa Z, Bonetto A, Costelli P, Minero VG, Penna F, Baccino FM, Lucia S, Rossi Fanelli F, Muscaritoli M. beta-hydroxy-beta-methylbutyrate (HMB) attenuates muscle and body weight loss in experimental cancer cachexia. Int J Oncol. 2011 Mar;38(3):713-20. doi: 10.3892/ijo.2010.885. Epub 2010 Dec 23.
PMID: 21184031
citation: Gerlinger-Romero F, Guimaraes-Ferreira L, Giannocco G, Nunes MT. Chronic supplementation of beta-hydroxy-beta methylbutyrate (HMbeta) increases the activity of the GH/IGF-I axis and induces hyperinsulinemia in rats. Growth Horm IGF Res. 2011 Apr;21(2):57-62. doi: 10.1016/j.ghir.2010.12.006. Epub 2011 Jan 14.
PMID: 21237681
citation: Aversa Z, Alamdari N, Castillero E, Muscaritoli M, Rossi Fanelli F, Hasselgren PO. beta-Hydroxy-beta-methylbutyrate (HMB) prevents dexamethasone-induced myotube atrophy. Biochem Biophys Res Commun. 2012 Jul 13;423(4):739-43. doi: 10.1016/j.bbrc.2012.06.029. Epub 2012 Jun 13.
PMID: 22705301
responsible party type: Principal Investigator
investigator affiliation: University of Roma La Sapienza
investigator full name: Manuela Merli
investigator title: Professor
mesh term: Sarcopenia