Growth Hormone in Decompensated Liver Cirrhosis

Sarcopenia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05253287
• Other study ID #: IEC-06/2021-2015
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: February 1, 2022
• Est. completion date: January 2025

Study information

• Verified date: March 2022
• Source: Postgraduate Institute of Medical Education and Research
• Contact: Nipun Verma, DM
• Phone: 9914208562
• Email: nipun29j[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: January 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Age above 18 years.

2. Patients having confirmed diagnosis of decompensated cirrhosis, any etiology.

3. Patients having given an informed and written consent for participation in the study.

Exclusion Criteria:

1. Acute on chronic liver failure.

2. Diagnosis of concomitant hepatocellular carcinoma or other active malignancy.

3. Severe cardiac dysfunction NYHA grade III/IV, Chronic obstructive pulmonary disease GOLD C or above.

4. Active alcohol abuse in last 3 months.

5. Known hypersensitivity to GH.

6. Human immunodeficiency virus seropositivity.

7. Patients on antiviral therapy for HCV, HBV or corticosteroid for autoimmune hepatitis those who have received it within the last 6 months.

8. TIPS insertion within 6 months prior to study inclusion.

9. Pregnancy & lactation.

10. Uncontrolled diabetes (Hb A1c = 9) or diabetic retinopathy.

11. Active sepsis.

Related Conditions & MeSH terms

• Digestive System Disease
• Digestive System Diseases
• End Stage Liver Disease
• Fibrosis
• Gastrointestinal Diseases
• Growth Hormone Treatment
• Liver Cirrhosis
• Liver Diseases
• Physiological Effect of Drugs
• Sarcopenia

Intervention

Drug:
• Growth Hormone
GH therapy will be initiated at a low dose of 2U/day and titrated slowly based on IGF-1 levels) subcutaneously for 1 year.

Locations

Country	Name	City	State
India	Postgraduate Institute of Medical education and Research	Chandigarh	UT

Sponsors (1)

Lead Sponsor	Collaborator
Postgraduate Institute of Medical Education and Research

Country where clinical trial is conducted

India, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complication free survival	Complications of cirrhosis - Ascites, Hepatic encephalopathy, Gastrointestinal bleeding, Bacterial infections, Acute kidney injury	12 Month
Primary	Transplant free survival	Transplant free survival where event is transplant or death	12 Month
Primary	Incidence of complications of cirrhosis and infections	Complications of cirrhosis - Ascites, Hepatic encephalopathy, Gastrointestinal bleeding, Bacterial infections, Acute kidney injury	12 Month
Primary	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
Primary	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
Primary	Treatment related adverse events	Any adverse events related to growth hormone	12 Month
Secondary	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
Secondary	Change in liver frailty index	LFI (Liver frailty index) will be calculated by FrAILT software©	12 Month
Secondary	Change in nitrogen balance	Nitrogen balance will be calculated by using formula - Nitrogen intake - nitrogen output	12 Month
Secondary	Change in myostatin levels	Myostatin in the serum will be measured in serum	12 Month
Secondary	Change in Functional capacity of monocytes	Phagocytic capacity of monocytes will be assessed using flow cytometry	12 Month
Secondary	Change in Functional capacity of Neutrophils	Phagocytic capacity of neutrophils will be assessed using flow cytometry	12 Month
Secondary	Change in cytokine levels	Pro-inflammatory and anti-inflammatory cytokines will be assessed in serum using Multiplex ELISA.	12 Month
Secondary	Immunophenotyping of T cells	Immunophenotyping of T cells will be performed using flow-cytometry.	12 Month
Secondary	Immunophenotyping of B cells	Immunophenotyping of B cells will be performed using flow-cytometry.	12 Month
Secondary	Immunophenotyping of NK cells	Immunophenotyping of NK will be performed using flow-cytometry.	12 Month
Secondary	Immunophenotyping of monocytes	Immunophenotyping of monocytes will be performed using flow-cytometry.	12 Month
Secondary	Immunophenotyping of neutrophils	Immunophenotyping of neutrophils will be performed using flow-cytometry.	12 Month
Secondary	Change in cell death markers	Markers of cell death - M30 & M65 will be assessed in serum using ELISA	12 Month
Secondary	Change in surrogate markers for hepatic regeneration	surrogate markers for hepatic regeneration- Hepatocytes growth factor will be assessed in serum using ELISA.	12 Month