An interventional study of Ensure Plus Advance and Ensure High Protein in Sarcopenia, Cirrhosis and Malnutrition, sponsored by Instituto Aragones de Ciencias de la Salud. Completed at 1 site in Spain. Open to participants aged 18 Years to 99 Years. Per ClinicalTrials.gov, last updated 2021-05-04.
Sponsored by Instituto Aragones de Ciencias de la Salud · Not applicable, Interventional, and Treatment
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.
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,
1,329 studies on the registry are indexed under Sarcopenia; 420 are open to participants now.
This study's enrollment of 43 is below the median of 60 across 855 interventional studies indexed under Sarcopenia.
Browse Sarcopenia studies →Instituto Aragones de Ciencias de la Salud is the lead sponsor of 11 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
Dietary Supplement: Ensure Plus Advance
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
Dietary Supplement: Ensure High Protein
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).
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).
Changes in body composition
changes in body composition, in particular in fat and muscle, will be assessed by bioelectrical impedance analysis (BIA)
Time frame: Baseline, 6 wk, and final (12 wk)
Liver Status I
Child-Pugh Score
Time frame: Baseline, 6 wk, and final (12 wk)
Liver Status II
Liver transaminase enzymes: gamma glutamyl transpeptidase (GGT), aspartate transaminase (AST), and alanine transaminase (ALT) will be combined in a liver functionality score
Time frame: Baseline, 6 wk, and final (12 wk)
Nutritional Status I
plasma HMB
Time frame: Baseline, 6 wk, and final (12 wk)
Nutritional Status II
Plasma lipids: total cholesterol, triglycerides, LDL\&HDL-cholesterol, free fatty acids
Time frame: Baseline, 6 wk, and final (12 wk)
Nutritional Status III
Plasma glucose and insulin will be combined to calculate the homeostatic model assessment (HOMA)
Time frame: Baseline, 6 wk, and final (12 wk)
Inflammation
C reactive protein
Time frame: Baseline, 6 wk, and final (12 wk)
Plan to share: Undecided
Ran from Oct 2017 to primary completion in Mar 2018, 5 months.
Of 492 non-industry interventional studies with no phase under Sarcopenia, half reached primary completion within 18 months of starting (the median), counting those still running; a quarter within 8 and three quarters within 34. This study's 5 months is below that.
Counting every sponsor, half of 503 studies reached it within 18 months; a quarter within 8 and three quarters within 34.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in May 2021. You cannot join it, but the record below documents what was studied.
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Instituto Aragones de Ciencias de la Salud