Refractory Ascitis Diagnosis by the Study of Labelled Albumin Pharmacokinetics

Study Overview
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Brief Summary
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Refractory ascites is an indication for liver transplantation, and includes ascites that is resistant to, or intractable by diuretic therapy (International Ascites Club). This definition is partly subjective; it can be established only a posteriori, following diuretic therapy administration to all patients, including those in whom untoward effects are prominent; and requires prolonged follow-up. An early diagnosis of refractory ascites would avoid giving diuretic therapy to patients in whom it will fail and identify rapidly candidates to liver transplantation. Such diagnosis could be done with a pharmacokinetic (PK) study of radiolabeled albumin between the peritoneal cavity and serum.

Detailed Description
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Main objective: assess the performances of PK parameters (transfer of labelled albumin) between peritoneal and vascular compartments, for the diagnosis of refractory ascitis, in patients with cirrhosis and abundant ascitis. Design: proof of concept study. Interventional cross-sectional study in Beaujon Hospital (Clichy, France), 1 recruiting center and 1 non recruiting center. Patients are recruited in the Hepatology department (Pr Valla) and PK exploration is performed in the nuclear medicine department (Pr Lebtahi) of Beaujon Hospital. Description of intervention: diuretics treatment discontinuation 7 days before exploration for patients with sensitive ascitis, and more than 7 days for those with refractory ascitis. The day of exploration, the patients come to hospital and stay in lying position. One intra-veinous injection of 0,015 megabecquerel(MBq) /Kg labelled human serum albumin (Iode-125 (125-I), Séralb®CisBio), in compliance with market authorization, simultaneously to one intra-peritoneal injection of 200 MBq of labelled albumin (Technetium 99m (99m-Tc), Vasculocis®, Cisbio), off-label used. It follows 5 minutes mobilization of the patient (right and left lateral decubitus), then a scintigraphy will be performed using a gamma-camera Symbia T2 (Siemens®). Repeated blood (5 ml) and peritoneal ascitis (3 ml) samples are performed before injection and every 30 minutes for 6 hours (catheter in place). Diuretic treatment can be restarted the day after PK explorations. Patients are followed-up at 1 month by phone call (for the collection of adverse events). Measurements : radioactivity measurements of 99m-Tc and 125-I in the biological samples are performed by a counter device in the nuclear medicine department (Wizard 3000, Packard®). Unidirectional transfer of labelled albumin (125-I) from vascular compartment (plasma-P) to peritoneal compartment (ascitis-A) (TPA), Unidirectional transfer of labelled albumin (99m-Tc) from peritoneal (A) to vascular compartment (P) (TAP), and the ratio TPA/TAP are calculated from these measurements using Matlab®.The gold standard is defined by the diagnosis of refractory ascitis performed before inclusion. Statistical analyses: performances of the TAP, of the TPA, and of the ratio TPA/TAP for the diagnosis of refractory ascitis, will be computed using the Receiver Operating Characteristic (ROC) curve. Number of patients : 30 patients (15 patients with refractory ascitis and 15 patients with sensitive or untreatable ascitis) will be included during a 24 months period (1 or 2 patients per month), and followed-up for 2 months. The PK explorations will be performed in nuclear medicine department not more than 4 weeks after inclusion. Total length of study will be of 26 months.

Official Title
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Refractory Ascitis Diagnosis by the Study of Labelled Albumin Pharmacokinetics Between Peritoneal and Vascular Compartments

Conditions
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Refractory Ascites in Patients With Cirrhosis

Intervention / Treatment
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* Radiation: labelled human serumalbumin (125-I, Séralb®CisBio)
* Radiation: labelled albumin (99m-Tc, Vasculocis®, Cisbio)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients consulting in Hepatology department of Beaujon Hospital aged 18 - 80 years old cirrhosis due to alcoholic and/or dysmetabolic and/or viral (HBV or HCV) cause, pathologically or clinically/biologically/radiologically proven. Volume of ascitis >5 L, either sensible or refractory to diuretics drugs according IAC criteria Exclusion Criteria: infection in the 2 weeks prior to inclusion (suspected or proven) upper gastrointestinal bleeding du to portal hypertension in the 2 weeks prior to inclusion transjugular intrahepatic portosystemic shunt (TIPS) advanced hepatocellular carcinoma hepatic transplantation unability to stay lying for 6 hours pregnancy / lactation renal deficiency (creat. clearance < 60ml/min) cardiac deficiency (≥ New York Heart Association (NYHA) III) or myocardial infarction (<3 months) other cause of ascitis contra-indication to human albumin (125-I) or vasculosis (99m-Tc) or other component of radio-pharmaceutics no health insurance coverage unability to go to the hospital for 1 day of exams refuse to consent to study participation

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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ascites in Patients With Cirrhosis<br>Patients will be further classified according to the refractory or sensitive ascitis | Radiation: labelled human serumalbumin (125-I, Séralb®CisBio)<br>* Intra-veinous injection of 0,015 MBq/Kg ; 0,5 to 2 mL injected over less than a minute<br>Radiation: labelled albumin (99m-Tc, Vasculocis®, Cisbio)<br>* intra-peritoneal injection of 200 MBq of labelled albumin (99m-Tc, Vasculocis®, Cisbio) ; 5 ml injected over less than a minute<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnosis of refractory ascitis according to International Ascites Club (IAC) |  | Exploration day (4 weeks after the inclusion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of pharmacokinetics parameters : TPA | radioactivity measurements of labelled albumin (125-I) in ascitis (peritoneal samples) and plasma (blood samples) | Exploration day (4 weeks after the inclusion) | 
| Measure of pharmacokinetics parameters : TAP | radioactivity measurements of labelled albumin (99m-Tc) in ascitis (peritoneal samples) and plasma (blood samples) | Exploration day (4 weeks after the inclusion) | 
| Measure of pharmacokinetics parameters | Ratio TPA/TAP | Exploration day (4 weeks after the inclusion) | 
| adverse events | Phone call | 1 month after exploration day | 
| Proportion of patients in whom examination conditions and technical feasibility were completed | adequate volume of ascites,stable state of patient, satisfactory spread of radiopharmaceuticals in the peritoneal compartment measure by scintigraphy, number of peritoneal and blood samples performed | Exploration day (4 weeks after the inclusion) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diagnostic performances, ascites