Clinical trial NCT03234920: Beta-Hydroxy-Beta-Methylbutyrate (HMB) Supplementation After Liver Transplantation
Official title: Effects of Beta-hydroxy-beta-methylbutyrate (HMB) Supplementation After Liver Transplantation: Randomized and Controlled Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Sarcopenia
Keywords: cirrhosis
liver transplantation
HMB
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2017-08-01
Enrollment: 22
Sex: MALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 1. Liver transplantation

Exclusion Criteria:

* 1. Multiple organ transplantation
* 2. Low compliance

Primary outcomes:
measure: Changes in Fat Free Mass Index 3-4 months after transplantation
timeFrame: 3-4° months after transplantation
Secondary outcomes:
measure: Changes in Fat Free Mass Index 6 and 12 months after transplantation
timeFrame: 6° and 12° months after transplantation
measure: Changes in 6MWT at 3-4, 6 and 12 months after transplantation
timeFrame: 3°-4°, 6° and 12° months after transplantation
measure: Changes in test-TUGT at 3-4, 6 and 12 months after transplantation
timeFrame: 3°-4°, 6° and 12° months after transplantation
measure: Changes in HG Test at 3-4, 6 and 12 months after transplantation
timeFrame: 3°-4°, 6° and 12° months after transplantation
measure: Evaluation of days of hospitalization during the study period
timeFrame: 3°-4°, 6° and 12° months after transplantation
measure: Evaluation of onset of metabolic syndrome after liver transplantation classified sec. APT III classification
timeFrame: 3°-4°, 6° and 12° months after transplantation
measure: Incidence of Treatment-Emergent Adverse Events evaluated to analog-visual scale
timeFrame: 3°-4°, 6° and 12° months after transplantation
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Gastroenterology Department, Sapienza University of Rome
Study officials:
affiliation: University of Roma La Sapienza
name: Manuela Merli, Prof
role: PRINCIPAL_INVESTIGATOR
References:
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: 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.
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: 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: 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: 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.