Clinical trial NCT05420753: Body Composition Changes After TIPS and Associated Clinical Outcomes
Official title: Single-center Randomized Controlled Trial to Evaluate Body Composition Changes and Clinical Outcomes After Transjugular Intrahepatic Portosystemic Shunt (TIPS) Creation in Patients With Cirrhosis and Complications of Portal Hypertension Awaiting Liver Transplantation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Cirrhosis, Liver
Sarcopenia
Keywords: cirrhosis
liver transplantation
sarcopenia
frailty
Lead sponsor: Oregon Health and Science University
Sponsor class: OTHER
First posted: 2022-06-15
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to prospectively assess the impact of TIPS creation on muscle mass and physical function in patients with cirrhosis, and to determine whether these changes correlate with improved outcomes in patients awaiting liver transplantation. Retrospective observational studies have shown improvement in muscle mass and body composition in cirrhotic patients undergoing TIPS. The investigators aim to now prospectively study this through a pilot randomized controlled trial tracking patients managed with TIPS creation compared to those managed without TIPS to determine whether these observational findings can be seen in a randomized cohort. The investigators hypothesize that TIPS creation will lead to improved muscle mass, body composition and muscle function within the first 12 months after the procedure compared to a control group without TIPS, and that these changes will improve liver disease outcomes in patients awaiting liver transplantation.

Detailed description: Sarcopenia (loss of muscle mass) and frailty (loss of muscle function) have increasingly become recognized as major prognostic factors in predicting morbidity and mortality with several disease states, including cirrhosis. Cirrhosis represents end-stage liver disease and is complicated by a multitude of clinical sequelae, such as variceal hemorrhage, ascites, renal insufficiency, hepatic encephalopathy, hepatopulmonary syndrome, cardiac dysfunction, infection and hepatocellular carcinoma. To date, liver transplantation remains the only prospect for a curative treatment. As the liver is the primary metabolic organ, sarcopenia is prevalent in cirrhosis, afflicting 30-70% of patients. Observational studies have implicated sarcopenia as an independent risk factor for morbidity and mortality in all clinical sequelae of cirrhosis. Moreover, sarcopenia and frailty have been shown to increase morbidity and mortality of transplant eligible patients on the liver transplant waitlist, as well as mortality of patients after liver transplant. Given the prevalence of sarcopenia and frailty in this patient population, and the severe clinical impacts, addressing these adverse predictors may have profound implications for the outcomes of patients with cirrhosis.

Cirrhosis often leads to portal hypertension, complications of which include lower extremity edema, ascites, hepatic hydrothorax, variceal bleeding, portal hypertensive gastropathy, portal vein thrombosis, and hepatic encephalopathy. Patients with cirrhosis and complications of portal hypertension are currently managed in several ways in clinical practice:

* medical management, including diuretics and non-selective beta blocker therapy
* endoscopic options include variceal banding or glue embolization
* invasive options include large-volume paracentesis (LVP) or transjugular intrahepatic portosystemic shunt (TIPS) creation.

Since 1988, the Liver Transplant Program at OHSU has been successfully treating waitlisted cirrhotic patients with complications of portal hypertension using a combination of these therapies. TIPS creation, particularly in the current era of stent grafts with a dedicated device for this procedure, has been a part of managing patients with cirrhosis as a bridge to transplant for two decades. Depending on the indication, patients can be treated with a combination of these therapies often with significant overlap. For example, a given patient with portal hypertension and ascites may be managed with diuretics and serial LVP vs. TIPS creation, and a given patient with variceal bleeding may be treated with beta-blockers and endoscopic banding vs. TIPS creation.

Of relevance to the proposed trial, recent observational studies have demonstrated significant reversal of sarcopenia after TIPS creation, and this reversal has been strongly correlated with improved survival and less hepatic encephalopathy. Moreover, the time course of muscle gains has been observed to occur within the first 6 months of TIPS creation, critical for patients awaiting liver transplantation, as benefits would occur during typical transplant waitlist time periods. Thus, TIPS creation may represent a major unmet need to address sarcopenia and frailty in patients with cirrhosis, and represents an intervention with potential to reverse this debilitating condition and improve clinical outcomes. Putative mechanisms for how TIPS creation may improve body composition include decreased congestive enteropathy resulting in improved gut nutrient absorption, decrease in metabolic burden from a hyperdynamic cardiopulmonary status in the setting of fluid overload, improvement in renal function, and changes in the gut microbiome resulting in conversion from a catabolic to an anabolic state. A major gap in knowledge, however, remains whether TIPS creation can directly reverse muscle loss. Furthermore, whether reversal of muscle loss results in improved measures of strength, physical performance and clinical outcomes has not been prospectively studied. In this proposal, the investigators plan to address this major knowledge gap through a pilot prospective randomized controlled trial tracking patients managed with TIPS creation compared to those managed without TIPS to determine whether these observational findings can be seen in a randomized cohort.

Eligibility criteria: Inclusion Criteria:

* Patients \>18 \<99 with cirrhosis wait listed for liver transplantation
* Evidence of complications of portal hypertension:
* Ascites or hydrothorax requiring escalation of diuretic medication
* Persistent ascites or hydrothorax despite diuretic use, or intolerance of diuretic use
* Gastrointestinal varices and blood loss anemia or history of variceal hemorrhage
* Portal hypertensive gastropathy and blood loss anemia
* Chronic portal vein thrombosis requiring recanalization and TIPS for transplant

Exclusion Criteria:

* Hepatocellular carcinoma or other active malignancy
* Recurrent overt hepatic encephalopathy
* Uncontrolled coagulopathy with maximum amplitude (MA) \<30 on thromboelastography
* Bacteremia or sepsis
* MELD \> 25
* Pregnant
* Decisionally impaired individuals
* Need for emergency TIPS creation
* Patients who do not have acceptable alternatives to TIPS creation to manage their disease

Primary outcomes:
measure: Body composition changes
timeFrame: Start to 2 years after enrollment
measure: Short Performance Physical Battery test
timeFrame: Start to 6 months after enrollment
measure: Liver Frailty test
timeFrame: Start to 6 months after enrollment
Secondary outcomes:
measure: Chronic Liver Disease Quality of Life Questionnaire
timeFrame: Start to 6 months after enrollment
measure: Overall survival
timeFrame: Start to 2 years after enrollment
measure: Transplant complications
timeFrame: Start to 30 days after transplant
measure: Cardiac function
timeFrame: Start to 6 months after enrollment
measure: Liver function tests
timeFrame: Start to 6 months after enrollment
measure: Cardiac mass
timeFrame: start to 6 months after enrollment
measure: Serum ammonia
timeFrame: start to 6 months after enrollment
measure: Serum glucose
timeFrame: start to 6 months after enrollment
Other outcomes:
measure: Stool microbiome genomic assessment
timeFrame: Start to 6 months after enrollment
measure: Lipocalin-2 biomarker assessment
timeFrame: Start to 6 months after enrollment
measure: IL-6 biomarker assessment
timeFrame: Start to 6 months after enrollment
measure: Salivary cortisol biomarker assessment
timeFrame: Start to 6 months after enrollment
Locations:
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
Study officials:
References: