Liver Disease ChronicNCT05956015
Albumin Catabolic Rate Measured by a Stable Isotope
A study testing stable isotopes in people with Liver Disease Chronic, run by Ake Norberg at 1 site in Sweden.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 40 years and olderHealthy volunteers can take part
- Conditions the study is for
- Liver Disease Chronic
- What is being tested?
- stable isotopes
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteSweden
- Study dates
- 28 Aug 2023to 31 Dec 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Sweden1 site
Karolinska Institutet
Stockholm, 14186
Åke Norberg, PhD, +46739669523, ake.norberg@ki.se
Olav Rooyackers, Professor, +46739661645, olav.rooyackers@ki.se
About this study
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.
Read the 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.
- Conditions
- Liver Disease Chronic
- Being tested
- stable isotopes
- Keywords
- albumin catabolism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
stable isotopesOther
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.
| Study group | Role | What they receive |
|---|---|---|
| Patients with liver disease | Experimental | 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. Receives: Other: stable isotopes |
| Healthy volunteers with no signs of liver disease | Experimental | 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. Receives: Other: stable isotopes |
What is being measured
The primary outcome is the main question the study is designed to answer.
Albumin degradation rate by stable isotope
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.
Measured: 12 weeks
Albumin degradation rate by different methods
Healthy volunteers will be compared to historical controls from our laboratory where albumin degradation rate was measured by radio-iodinated human serum albumin.
Measured: 12 weeks
Secondary outcomes (3)
Albumin synthesis rate
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.
Measured: 120 minutes
Albumin degradation by modeling different fractions of oxidized albumin over time
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
Measured: 12 weeks
Correlation between oxidation and degradation rate of albumin
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.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jul 2023
- Study start28 Aug 2023 (estimated)
- Primary completion30 Jun 2028 (estimated)
- Study completion31 Dec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Liver Disease ChronicStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Ake Norberg
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Ake Norberg, Karolinska Institutet
- Investigators
- Åke Norberg, PhD, Principal investigator, Karolinska Institutet, Stockholm
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05956015
- Sponsor's protocol ID
- 4-2885/2022
- Other IDs
- K2022-10941
- Status last verified
- Jul 2023
- First submitted
- 13 Jul 2023
- Last updated
- 25 Jul 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Albumin Catabolic Rate Measured by a Stable Isotope
- ClinicalTrials.gov ID
- NCT05956015
- Acronym / sponsor ID
- 4-2885/2022
- Conditions
- Liver Disease Chronic
- Keywords
- albumin catabolism
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- Ake NorbergUniversity, hospital or other
- Study start
- 28 Aug 2023 (estimated)
- Primary completion
- 30 Jun 2028 (estimated)
- Study completion
- 31 Dec 2028 (estimated)
- First posted
- 21 Jul 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Patients with liver disease | Experimental | Other: stable isotopespatients 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. |
| Healthy volunteers with no signs of liver disease | Experimental | Other: stable isotopesHealthy 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. |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- males and females >= 40 years (to be more like the anticipated age of the liver patients)
- good peripheral blood vessels
- written informed consent
- known compensated liver cirrhosis with radiological or endoscopic signs of portal hypertension, such as varices, splenomegaly, or shunts.
- written informed consent
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| stable isotopesThe 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. | Other | Healthy volunteers with no signs of liver disease, Patients with liver disease |
Primary outcome
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.
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.
3 secondary outcomes
Albumin synthesis rate
Time frame: 120 minutes
Albumin degradation by modeling different fractions of oxidized albumin over time
Time frame: 12 weeks
Correlation between oxidation and degradation rate of albumin
Time frame: 12 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jul 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Åke Norberg, PhD principal investigator
Karolinska Institutet, Stockholm
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing stable isotopes in people with Liver Disease Chronic, run by Ake Norberg at 1 site in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 25 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Åke Norberg, PhD (+46739669523, ake.norberg@ki.se), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Albumin degradation rate by stable isotope (time frame: 12 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jul 2023.