Clinical trial NCT05253287: Growth Hormone in Decompensated Liver Cirrhosis
Official title: Impact of Repurposed Growth Hormone Treatment on Clinical, Nutritional, Immunological and Regenerative Parameters in Decompensated Liver Cirrhosis: a Randomized Control Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Liver Cirrhosis
Fibrosis
End Stage Liver Disease
Digestive System Disease
Physiological Effect of Drugs
Growth Hormone Treatment
Sarcopenia
Keywords: Decompensated liver cirrhosis
Growth hormone
Lead sponsor: PGIMER
Sponsor class: UNKNOWN
First posted: 2022-02-23
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Group 1 - Growth Hormone + Standard medical therapy Group 2 - Standard Medical Therapy
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Complication free survival
timeFrame: 12 Month
measure: Transplant free survival
timeFrame: 12 Month
measure: Incidence of complications of cirrhosis and infections
timeFrame: 12 Month
measure: Change in disease severity scores (CTP score)
timeFrame: 12 Month
measure: Change in disease severity scores (MELD Na)
timeFrame: 12 Month
measure: Treatment related adverse events
timeFrame: 12 Month
Secondary outcomes:
measure: Assessment of sarcopenia
timeFrame: 12 Month
measure: Change in liver frailty index
timeFrame: 12 Month
measure: Change in nitrogen balance
timeFrame: 12 Month
measure: Change in myostatin levels
timeFrame: 12 Month
measure: Change in Functional capacity of monocytes
timeFrame: 12 Month
measure: Change in Functional capacity of Neutrophils
timeFrame: 12 Month
measure: Change in cytokine levels
timeFrame: 12 Month
measure: Immunophenotyping of T cells
timeFrame: 12 Month
measure: Immunophenotyping of B cells
timeFrame: 12 Month
measure: Immunophenotyping of NK cells
timeFrame: 12 Month
measure: Immunophenotyping of monocytes
timeFrame: 12 Month
measure: Immunophenotyping of neutrophils
timeFrame: 12 Month
measure: Change in cell death markers
timeFrame: 12 Month
measure: Change in surrogate markers for hepatic regeneration
timeFrame: 12 Month
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical education and Research
state: UT
Study officials:
affiliation: Professor and Head, Department of Hepatology
name: Virendra Singh, DM
role: STUDY_DIRECTOR
References: