- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05956015
Albumin Catabolic Rate Measured by a Stable Isotope
The goal of this physiological study is to compare albumin catabolic rate measured by a stable isotope labeled amino acid in healthy volunteers and in patients with liver disease. At steady state synthesis and catabolism or degradation are equal.
The primary questions it aims to answer are:
- Is albumin catabolic rate lower in patients with liver disease?
- Is albumin catabolic rate measured by stable isotopes in volunteers like historical controls measured by radio-iodinated albumin at the investigator's laboratory or elsewhere? Subjects will be given an oral dose of the deuterium labeled amino acid phenylalanine that will be incorporated by the liver in newly synthetized albumin molecules, and blood samples will be taken over 12 weeks to determine the catabolic rate of albumin.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This study is part of a greater research program investigating the clinical use of albumin infusions in surgery, liver disease and states of critical illness. Indications are still under debate after more than 70 years of use. Good methodology for assessment of synthesis or degradation can be of immense value in these situations.
The gold standard to assess albumin turn-over is to use radio-iodine labeled albumin and take blood samples over several weeks. This method is however associated with many regulatory difficulties and possibly also methodological flaws.
Intravenous injection of deuterium labeled D5-phenylalanine has been used for snap-shot assessment of albumin synthesis, but in this study the stable isotope tracer will be given orally. The idea is that a large dose of labeled phenylalanine will over-flow all body compartments and thus in the liver be incorporated in the newly synthetized albumin molecules. After a short time period there is no more tracer in the amino acid pool and the disappearance of labeled albumin molecules can then be used to measure the albumin disappearance rate, that is equal to the catabolic rate and in steady state also equal to the synthesis rate.
The investigaors believe that by this new method it is possible to overcome some of the issues of radio-iodinated albumin: 1) no radiation, 2) no risk that the tracer leaves from the albumin molecule ahead of the catabolism of the albumin molecule, 3) no risk that the half-life of the albumin molecule is damaged by the labeling process, 4) a potential to measure turn-over of other long-lasting proteins.
Quantitative measurement of enrichment of isotopically labeled phenylalanine is done using gas chromatography-mass spectrometry at the Karolinska Stable Isotope Core where Olav Rooyackers is the laboratory director. Quantification of total phenylalanine (the precursor) is performed by mass spectrometry against an internal standard.
The albumin molecule binds to free acid radicals (scavenger function) with its sulfhydryl group in the Cys-34 position (human mercaptoalbumin). During oxidative stress, the sulfhydryl group is oxidized to sulfinic acid (human non-mercaptoalbumin 1, HNA 1). This is a reversible process. Upon continued oxidation, sulfonic acid is formed, which appears to be irreversible (human non-mercaptoalbumin 2, HNA2). The result is a damaged albumin molecule that has lost its scavenger function. Oxidative stress with high levels of HNA2 may have a decisive role in the pathogenesis of severe liver failure.
There is no data in the literature regarding changes in oxidized albumin over time. The investigators will try to model albumin turnover by looking at how these fractions and the proportions between them change over time. Previous results, suggesting that the amount of oxidized albumin is higher in patients with liver cirrhosis [Oettl 2013], will be reproduced. Finally, the association between albumin oxidation and albumin catabolic rate will be described.
The statistical analysis plan including the determination of the number of study subjects is included in the attached study plan.
Study Type
Enrollment (Estimated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Åke Norberg, PhD
- Phone Number: +46739669523
- Email: ake.norberg@ki.se
Study Contact Backup
- Name: Olav Rooyackers, Professor
- Phone Number: +46739661645
- Email: olav.rooyackers@ki.se
Study Locations
-
-
-
Stockholm, Sweden, 14186
- Karolinska Institutet
-
Contact:
- Åke Norberg, PhD
- Phone Number: +46739669523
- Email: ake.norberg@ki.se
-
Contact:
- Olav Rooyackers, Professor
- Phone Number: +46739661645
- Email: olav.rooyackers@ki.se
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
Healthy volunteers:
- males and females >= 40 years (to be more like the anticipated age of the liver patients)
- good peripheral blood vessels
- written informed consent
Patients with liver cirrhosis:
- known compensated liver cirrhosis with radiological or endoscopic signs of portal hypertension, such as varices, splenomegaly, or shunts.
- written informed consent
Exclusion Criteria:
- Planned surgical procedure within 3 months (due to possible blood loss i.e. loss of tracer)
- Pregnancy at dosing
- Phenylketonuria
- Participating in other study with stable isotopes within 60 days.
- Circumstance that causes the responsible researcher to assess the research person's participation as inappropriate
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Patients with liver disease
patients with chronic liver disease will receive a oral dose of a stable isotope labeled amino acid, 2H5-Phenylalanine, (45 mg/kg body weight 50% MPE). Blood samples will be taken over 12 weeks. |
The tracer 2H5-phenylalanine is an essential amino acid labeled with deuterium that is a stable isotope, i.e. no radiation is emitted, but the tracer can still be assessed by a combination of gas chromatography and mass spectrometry.
The tracer has no measurable effects, but are used for assessment of human physiology.
|
Experimental: Healthy volunteers with no signs of liver disease
Healthy volunteers with no signs of liver disease will receive a oral dose of a stable isotope labeled amino acid, 2H5-Phenylalanine, (45 mg/kg body weight 50% MPE). Blood samples will be taken over 12 weeks. |
The tracer 2H5-phenylalanine is an essential amino acid labeled with deuterium that is a stable isotope, i.e. no radiation is emitted, but the tracer can still be assessed by a combination of gas chromatography and mass spectrometry.
The tracer has no measurable effects, but are used for assessment of human physiology.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Albumin degradation rate by stable isotope
Time Frame: 12 weeks
|
The disappearance rate of 2H5-phenylalanine labeled albumin over time, that is the catabolic rate of albumin, will be measured in both study groups in blood samples over 12 weeks, and the study groups compared.
|
12 weeks
|
Albumin degradation rate by different methods
Time Frame: 12 weeks
|
Healthy volunteers will be compared to historical controls from our laboratory where albumin degradation rate was measured by radio-iodinated human serum albumin.
|
12 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Albumin degradation by modeling different fractions of oxidized albumin over time
Time Frame: 12 weeks
|
During the life span of the albumin molecule more and more oxidation appears.
The doubly oxidized molecule can no longer reverse to unoxidized albumin.
We want to investigate if rations of labeled to unlabeled fractions of the different forms of oxidized albumin can be used for modeling albumin degradation rate
|
12 weeks
|
Correlation between oxidation and degradation rate of albumin
Time Frame: 12 weeks
|
Oxidation of albumin molecules has been reported to be increased in liver disease.
We want to see if there is a correlation between oxidation fraction and albumin degradation rate.
|
12 weeks
|
Albumin synthesis rate
Time Frame: 120 minutes
|
We will compare the oral flooding dose with historical controls where the isotope was given intravenously at our laboratory for measurement of albumin synthesis rates in volunteers and patients with liver disease.
|
120 minutes
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Åke Norberg, PhD, Karolinska Institutet, Stockholm
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 4-2885/2022
- K2022-10941 (Other Identifier: Karolinska University Hospital)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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