Growth Hormone in Decompensated Liver Cirrhosis

Study Overview
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Brief Summary
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Globally, cirrhosis and liver cancer carries a huge burden and accounts for about 3.5% (2 million) of all deaths every year. Once decompensated, i.e. development of ascites, variceal bleed, encephalopathy, and jaundice, the life expectancy is markedly reduced to a median of two years. The definitive treatment in this stage, i.e., liver transplantation is limited by cost, lack of donors, and life-long immunosuppression. In addition to complications due to portal hypertension and hepatic insufficiency, decompensated cirrhosis is associated with malnutrition, sarcopenia, immune dysfunction, and impaired regeneration. Patients with cirrhosis are growth hormone (GH) resistant, with reduced insulin-like growth factor, which are linked to malnutrition and poor liver regeneration in cirrhosis. Diverse preclinical and clinical investigations in vitro and in vivo, have shown a benefit of GH in GH deficient, elderly and HIV positive patients. GH therapy in cirrhosis has been shown to improve nitrogen economy and to improve the GH resistance in a small pilot study by Donaghy et al. Also, GH therapy of short duration has shown to increase IGF1 levels, IGFBP-3 levels in patients of cirrhosis. GH therapy has also been shown to improve liver regeneration and protein synthesis after hepatectomy in patients of HCC with cirrhosis. However, there is a scarcity of data on clinical impact of long term administration of GH therapy in patients of cirrhosis. Hence, we undertook the present study to study the effect of growth hormone on clinical outcomes, malnutrition, immune cells and liver regeneration in patients with cirrhosis.

Detailed Description
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Liver disease accounts for approximately 3.5% all deaths per year around the world, cirrhosis being the 11th most common cause of death globally. Liver cirrhosis is the final stage of all progressive and chronic liver diseases which progresses from asymptomatic compensated stage to decompensated at a rate of 5% to 7% each year. The major complications of liver cirrhosis are portal hypertension, ascites, spontaneous bacterial peritonitis (SBP), variceal bleed, hepatic encephalopathy (HE), hepatocellular carcinoma (HCC). Moreover, complications like protein-calorie malnutrition associated with sarcopenia, cirrhosis associated immune dysfunction (CAID) and impaired regeneration further adds to reduced survival. Liver transplantation is the only effective treatment for these patients but it is limited by resources, costs, expertise, and organ availability. Malnutrition is common in cirrhosis with prevalence ranging from 65 to 100%. Sarcopenia or loss of skeletal muscle mass is the major component of malnutrition in cirrhosis with prevalence of 40- 60%. Independent clinical consequences of sarcopenia in cirrhosis include lower survival, quality of life & increases risk of complications. Lack of improvement with nutritional supplementation is observed which may be attributed to GH resistance in cirrhotic patients further worsening sarcopenia. CAID is a dynamic phenomenon, comprised of both increased systemic inflammation and immunodeficiency, ultimately leading to 30% mortality. Immunodeficiency in cirrhosis roots from deranged local immunity of liver, compromised immune surveillance of the liver and impairments in systemic immune cells (innate as well as adaptive).The systemic inflammation results from persistent immune cell stimulation due to enhanced gut translocation leading to increased production of various proinflammatory cytokines. Liver regeneration is a complex and unique process. Hepatocytes have a remarkable capacity to meet the replacement demands during cellular loss. However, this regenerative capacity is overwhelmed during the late stage of acute liver injury, compromised in chronic liver injury, and lost in acute-on-chronic liver injury. GH administration have been shown to improve sarcopenia, immune functions & regeneration in clinical studies and preclinical studies both in vitro and in vivo. Patients with chronic liver diseases are GH resistant i.e. they have high GH levels & low levels of IGF-1. So, in this study, we will investigate the impact of growth hormone on additional parameters including clinical outcomes, immunological profile and select parameters of liver regeneration in decompensated liver cirrhosis.

Official Title
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Impact of Repurposed Growth Hormone Treatment on Clinical, Nutritional, Immunological and Regenerative Parameters in Decompensated Liver Cirrhosis: a Randomized Control Trial

Conditions
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Fibrosis, Liver Cirrhosis, End Stage Liver Disease, Digestive System Disease, Physiological Effect of Drugs, Growth Hormone Treatment, Sarcopenia

Intervention / Treatment
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* Drug: Growth Hormone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age above 18 years. Patients having confirmed diagnosis of decompensated cirrhosis, any etiology. Patients having given an informed and written consent for participation in the study. Exclusion Criteria: Acute on chronic liver failure. Diagnosis of concomitant hepatocellular carcinoma or other active malignancy. Severe cardiac dysfunction NYHA grade III/IV, Chronic obstructive pulmonary disease GOLD C or above. Active alcohol abuse in last 3 months. Known hypersensitivity to GH. Human immunodeficiency virus seropositivity. Patients on antiviral therapy for HCV, HBV or corticosteroid for autoimmune hepatitis those who have received it within the last 6 months. TIPS insertion within 6 months prior to study inclusion. Pregnancy & lactation. Uncontrolled diabetes (Hb A1c ≥ 9) or diabetic retinopathy. Active sepsis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Group 1 - Growth Hormone + Standard medical therapy Group 2 - Standard Medical Therapy
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard Medical treatment<br>Standard medical therapy: diuretics, lactulose, rifaximin, diuretics, albumin infusion, nutritional support (as required) | |
| Experimental: Growth hormone + Standard medical therapy<br>GH therapy will be initiated at a low dose of 2U/day and titrated slowly based on IGF-1 levels) subcutaneously for 1 year. | Drug: Growth Hormone<br>* GH therapy will be initiated at a low dose of 2U/day and titrated slowly based on IGF-1 levels) subcutaneously for 1 year.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complication free survival | Complications of cirrhosis - Ascites, Hepatic encephalopathy, Gastrointestinal bleeding, Bacterial infections, Acute kidney injury | 12 Month | 
| Transplant free survival | Transplant free survival where event is transplant or death | 12 Month | 
| Incidence of complications of cirrhosis and infections | Complications of cirrhosis - Ascites, Hepatic encephalopathy, Gastrointestinal bleeding, Bacterial infections, Acute kidney injury | 12 Month | 
| Change in disease severity scores (CTP score) | The Child-Turcotte-Pugh (CTP) score is used to assess the prognosis of patients with cirrhosis. The Pugh-Child score is determined by scoring five clinical measures of liver disease (Encephalopathy, Ascites, Albumin, Bilirubin and INR). A score of 1, 2, or 3 is given to each measure, with 3 being the most severe. | 12 Month | 
| Change in disease severity scores (MELD Na) | The MELD/Na score is a scoring system for accessing the severity of chronic liver disease using values as serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time and sodium, to predict survival. | 12 Month | 
| Treatment related adverse events | Any adverse events related to growth hormone | 12 Month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of sarcopenia | Sarcopenia will be assessed by calculation of Skeletal muscle index by taking cross sectional area of the psoas muscle at the level of the third lumbar vertebra on abdomen CT scans. | 12 Month | 
| Change in liver frailty index | LFI (Liver frailty index) will be calculated by FrAILT software© | 12 Month | 
| Change in nitrogen balance | Nitrogen balance will be calculated by using formula - Nitrogen intake - nitrogen output | 12 Month | 
| Change in myostatin levels | Myostatin in the serum will be measured in serum | 12 Month | 
| Change in Functional capacity of monocytes | Phagocytic capacity of monocytes will be assessed using flow cytometry | 12 Month | 
| Change in Functional capacity of Neutrophils | Phagocytic capacity of neutrophils will be assessed using flow cytometry | 12 Month | 
| Change in cytokine levels | Pro-inflammatory and anti-inflammatory cytokines will be assessed in serum using Multiplex ELISA. | 12 Month | 
| Immunophenotyping of T cells | Immunophenotyping of T cells will be performed using flow-cytometry. | 12 Month | 
| Immunophenotyping of B cells | Immunophenotyping of B cells will be performed using flow-cytometry. | 12 Month | 
| Immunophenotyping of NK cells | Immunophenotyping of NK will be performed using flow-cytometry. | 12 Month | 
| Immunophenotyping of monocytes | Immunophenotyping of monocytes will be performed using flow-cytometry. | 12 Month | 
| Immunophenotyping of neutrophils | Immunophenotyping of neutrophils will be performed using flow-cytometry. | 12 Month | 
| Change in cell death markers | Markers of cell death - M30 & M65 will be assessed in serum using ELISA | 12 Month | 
| Change in surrogate markers for hepatic regeneration | surrogate markers for hepatic regeneration- Hepatocytes growth factor will be assessed in serum using ELISA. | 12 Month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Decompensated liver cirrhosis, Growth hormone