End Stage Renal Failure on DialysisCarRAAT-2NCT02472834
Trial of Carbamylation in Renal Disease-Modulation With Amino Acid Therapy
A study testing Amino acid supplementation NephrAmine® in people with End Stage Renal Failure on Dialysis, run by Massachusetts General Hospital at 2 sites in United States.
Trial summary
Patients with end stage renal disease (ESRD) usually have high levels of urea that may interact with blood proteins and change their structure by a process known as carbamylation. Evidence suggests that high levels of carbamylated proteins may be linked to adverse outcomes in dialysis patients. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- End Stage Renal Failure on Dialysis
- What is being tested?
- Amino acid supplementation NephrAmine®
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 54 participants
- Where
- 2 sitesUnited States
- Study dates
- Feb 2016to Dec 2020
- Phase
- Interventional
- Are there results?
- None posted in the registry
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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Informed of the investigational nature of the study and sign written informed consent
- Willing and able to adhere to all study-related procedures, including adherence to study medication regimen
- ≥18 years old
- On stable medical therapy in the last 30 days before the study entry, defined as no change, addition, or removal of medications
- Patients must satisfy the following criteria based on the initial screening laboratory values:
- Serum albumin ≥ 3.0 g/dL (30 g/L)
Show all 12Show fewer
- Dialysis adequacy recorded as Kt/ V > 1.2
- Carbamylated albumin (C-Alb) > 7.7 mmol/mol
- Women of childbearing potential must be practicing barrier or oral contraception, for the duration of the study-related treatment, or be documented as surgically sterile or one year post-menopausal
- If female, be non-nursing, non-pregnant and have a negative pregnancy test within two weeks of starting study treatment
- On stable hemodialysis therapy for at least 90 days before the study entry, defined as receiving thrice weekly dialysis and carrying a diagnosis of ESRD
- Prescribed a dialysis treatment time of 4 hours per session
Who cannot join
- Taking any type of amino acid supplementation within the last 90 days
- Received parenteral nutrition within last 90 days
- History of allergy to any amino acid compound
- Poorly controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 110 mmHg during any of the previous 3 dialysis sessions (confirmed by repeat)
- Severe hepatic impairment
- HIV positive
Show all 11Show fewer
- Condition with prognosis <1 year at time of study entry
- Body Mass Index (BMI) <18 or >30
- Current active treatment in another investigational study or participation in another investigational study in the 1 month prior to screening
- Active malignancies or other serious concurrent or recent medical or psychiatric condition which, in the opinion of the Investigator, makes the patient unsuitable for participation in this study
- Presence of asthma
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
Fresenius Medical Centers (local affilliates)
Boston, Massachusetts, 02201
About this study
Official title: Amino Acid Therapy to Modify Protein Carbamylation in End Stage Renal Disease: A Randomized Trial
Patients with end stage renal disease (ESRD) usually have high levels of urea that may interact with blood proteins and change their structure by a process known as carbamylation. Evidence suggests that high levels of carbamylated proteins may be linked to adverse outcomes in dialysis patients. This is a randomized, open-label study to evaluate the effects of amino acid supplementation on levels of carbamylated proteins in ESRD patients. Secondary objectives will be to determine whether this intervention can modify intermediate markers of inflammation, cardiac stress, and erythropoietin responsiveness in this population. Sixty ESRD patients on dialysis will be randomized into two groups of 30 patients each. Group 1 will receive intravenous supplementation with an FDA-approved amino acid solution (250 mL of NephrAmine®, 5.4% amino acids) during regular dialysis sessions (3 times weekly for 8 weeks); Group 2 will be treated according to standard-of-care (no amino acid supplementation). During the 8 weeks of therapy and for 4 weeks of follow-up, blood will be drawn from patients' existing hemodialysis access ports (~20 mL once per month) to measure levels of carbamylated albumin, amino acids, selected biomarkers, and standard laboratory values. Patients randomized to Group 1 will have fluid volume equivalent to the amino acid therapy removed by ultra-filtration to avoid net fluid gain. All patients will be monitored for safety (adverse events) and for changes in hemodynamics and dialysis prescription.
Read the detailed description
As human kidney function declines, so does the kidney's ability to excrete urea, the chief end product of nitrogen metabolism. Excess urea may accelerate the pathophysiological consequences of kidney failure. Urea spontaneously dissociates to form cyanate, which, in its unprotonated form can react with protein amino groups in a process known as carbamylation. Carbamylation-induced protein alterations may be involved in the progression of various diseases by changing the structure, charge, and function of enzymes, hormones, receptors, and amino acids. For example, proteins such as collagen and low density lipoproteins (LDLs), when carbamylated, have been shown to induce the characteristic biochemical events of atherosclerosis progression. This research aims to evaluate whether amino acid supplementation can attenuate such processes that are known to contribute to morbidity in patients with ESRD.
Percent carbamylated albumin (C-Alb) level will be used as a measure of overall carbamylation burden. Previous studies conducted by MGH Investigators have shown a negative correlation between %C-Alb and circulating amino acids, suggesting that free amino acids may actively scavenge reactive isocyanate. Further, ex vivo studies show that amino acid supplementation reduces the carbamylation reaction. The MGH Investigators recently demonstrated an association between markers of cardiac stress, heart failure and carbamylation in patients with ESRD and found that %C-Alb was strongly associated with erythropoietin resistance in dialysis patients. Additionally, using validated measures of total-body carbamylation, these and other Investigators have reported that elevated protein carbamylation was linked with higher mortality in several distinct ESRD cohorts. Finally, preliminary data from a recent pilot study at MGH (NCT01612429) suggests that amino acid supplementation in patients with ESRD undergoing maintenance hemodialysis can attenuate carbamylation of proteins.
The proposed randomized study will directly evaluate the impact of amino acid supplementation on: (1) the burden of carbamylation in terms of %C-Alb; and (2) selected intermediate determinants of clinical outcomes, i.e., markers of inflammation, cardiac stress, and erythropoietin responsiveness.
- Conditions
- End Stage Renal Failure on Dialysis
- Being tested
- Amino acid supplementation NephrAmine®
- Keywords
- Carbamylation, Albumin, Protein structure, Kidney disease
- Medical subject headings
- Kidney Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Amino acid supplementation NephrAmine®Dietary supplement
Also called NephrAmine®
Dialysis patients will be randomized to receive either 250 mL of NephrAmine® (5.4% amino acids for injection; B. Braun Medical, Inc) containing ~14 grams of essential amino acids during each dialysis session (3 times weekly for 8 weeks) or no treatment (standard-of-care)
| Study group | Role | What they receive |
|---|---|---|
| Amino acid supplementation NephrAmine® | Experimental | 250 mL of 5.4% amino acid solution (NephrAmine) by intravenous infusion 3 x weekly for 8 weeks plus 4 weeks of follow-up. Receives: Dietary Supplement: Amino acid supplementation NephrAmine® |
| Standard-of-care | No intervention | Standard-of-care does not include amino acid supplementation, but this control arm will be evaluated for the same outcomes as the experimental arm for 8 weeks plus 4 weeks of follow-up |
What is being measured
The primary outcome is the main question the study is designed to answer.
Differences in plasma carbamylated albumin (C-Alb) levels
Measured: Baseline and weeks 4, 8, and 12
Secondary outcomes (4)
Safety of amino acid infusion
In terms of in terms of adverse events, changes in amino acid levels, ammonia, routine dialysis labs, intra-dialytic hemodynamics, and dialysis prescription during 8 weeks of therapy and 4 weeks of follow-up post-therapy
Measured: Baseline and weeks 4, 8, and 12
Differences in cardiac markers
Changes in Troponin T and NT-Pro-BNP during 8 weeks of therapy and 4 weeks of follow-up post-therapy
Measured: Baseline and weeks 4, 8, and 12
Differences in inflammatory markers
Changes in myeloperoxidase, IL-6, IL-12, IFN-γ, and TNF-α during 8 weeks of therapy and 4 weeks of follow-up post-therapy
Measured: Baseline and weeks 4, 8, and 12
Differences in erythropoietin resistance
Measured in terms of the erythropoietin responsiveness index (ERI, defined as average weekly erythropoietin dose [U]/ kg body weight/ average hemoglobin [g/dL]) (Kalim et al. 2013) during 8 weeks of therapy and 4 weeks of follow-up post-therapy
Measured: Baseline and weeks 4, 8, and 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2015 (estimated)
- Study startFeb 2016
- Primary completionDec 2020
- Study completionDec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for End Stage Renal Failure on DialysisStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 54 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Sahir Kalim, Massachusetts General Hospital
- Investigators
- Sahir Kalim, MD, MMSc, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02472834
- Sponsor's protocol ID
- 2015-P-000562
- Other IDs
- 5K23DK106479-04
- Acronym
- CarRAAT-2
- Status last verified
- Feb 2021
- First submitted
- 9 Jun 2015
- Last updated
- 24 Feb 2021
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
Drechsler C, Kalim S, Wenger JB, Suntharalingam P, Hod T, Thadhani RI, Karumanchi SA, Wanner C, Berg AH. Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease. Kidney Int. 2015 Jun;87(6):1201-8. doi: 10.1038/ki.2014.429. Epub 2015 Feb 11.
PubMed 25671766Kalim S, Tamez H, Wenger J, Ankers E, Trottier CA, Deferio JJ, Berg AH, Karumanchi SA, Thadhani RI. Carbamylation of serum albumin and erythropoietin resistance in end stage kidney disease. Clin J Am Soc Nephrol. 2013 Nov;8(11):1927-34. doi: 10.2215/CJN.04310413. Epub 2013 Aug 22.
PubMed 23970130Berg AH, Drechsler C, Wenger J, Buccafusca R, Hod T, Kalim S, Ramma W, Parikh SM, Steen H, Friedman DJ, Danziger J, Wanner C, Thadhani R, Karumanchi SA. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci Transl Med. 2013 Mar 6;5(175):175ra29. doi: 10.1126/scitranslmed.3005218.
PubMed 23467560Koeth RA, Kalantar-Zadeh K, Wang Z, Fu X, Tang WH, Hazen SL. Protein carbamylation predicts mortality in ESRD. J Am Soc Nephrol. 2013 Apr;24(5):853-61. doi: 10.1681/ASN.2012030254. Epub 2013 Feb 21.
PubMed 23431074
Study at a glance
From the registry record, last updated by the sponsor on 24 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Amino Acid Therapy to Modify Protein Carbamylation in End Stage Renal Disease: A Randomized Trial
- ClinicalTrials.gov ID
- NCT02472834
- Acronym / sponsor ID
- CarRAAT-2 / 2015-P-000562
- Conditions
- End Stage Renal Failure on Dialysis
- Keywords
- Carbamylation, Albumin, Protein structure, Kidney disease
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 54 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- Feb 2016 (actual)
- Primary completion
- Dec 2020 (actual)
- Study completion
- Dec 2020 (actual)
- First posted
- 16 Jun 2015 (estimated)
- 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.
Patients with end stage renal disease (ESRD) usually have high levels of urea that may interact with blood proteins and change their structure by a process known as carbamylation. Evidence suggests that high levels of carbamylated proteins may be linked to adverse outcomes in dialysis patients. This is a randomized, open-label study to evaluate the effects of amino acid supplementation on levels of carbamylated proteins in ESRD patients. Secondary objectives will be to determine whether this intervention can modify intermediate markers of inflammation, cardiac stress, and erythropoietin responsiveness in this population. Sixty ESRD patients on dialysis will be randomized into two groups of 30 patients each. Group 1 will receive intravenous supplementation with an FDA-approved amino acid solution (250 mL of NephrAmine®, 5.4% amino acids) during regular dialysis sessions (3 times weekly for 8 weeks); Group 2 will be treated according to standard-of-care (no amino acid supplementation). During the 8 weeks of therapy and for 4 weeks of follow-up, blood will be drawn from patients' existing hemodialysis access ports (~20 mL once per month) to measure levels of carbamylated albumin, amino acids, selected biomarkers, and standard laboratory values. Patients randomized to Group 1 will have fluid volume equivalent to the amino acid therapy removed by ultra-filtration to avoid net fluid gain. All patients will be monitored for safety (adverse events) and for changes in hemodynamics and dialysis prescription.
Detailed description
As human kidney function declines, so does the kidney's ability to excrete urea, the chief end product of nitrogen metabolism. Excess urea may accelerate the pathophysiological consequences of kidney failure. Urea spontaneously dissociates to form cyanate, which, in its unprotonated form can react with protein amino groups in a process known as carbamylation. Carbamylation-induced protein alterations may be involved in the progression of various diseases by changing the structure, charge, and function of enzymes, hormones, receptors, and amino acids. For example, proteins such as collagen and low density lipoproteins (LDLs), when carbamylated, have been shown to induce the characteristic biochemical events of atherosclerosis progression. This research aims to evaluate whether amino acid supplementation can attenuate such processes that are known to contribute to morbidity in patients with ESRD.
Percent carbamylated albumin (C-Alb) level will be used as a measure of overall carbamylation burden. Previous studies conducted by MGH Investigators have shown a negative correlation between %C-Alb and circulating amino acids, suggesting that free amino acids may actively scavenge reactive isocyanate. Further, ex vivo studies show that amino acid supplementation reduces the carbamylation reaction. The MGH Investigators recently demonstrated an association between markers of cardiac stress, heart failure and carbamylation in patients with ESRD and found that %C-Alb was strongly associated with erythropoietin resistance in dialysis patients. Additionally, using validated measures of total-body carbamylation, these and other Investigators have reported that elevated protein carbamylation was linked with higher mortality in several distinct ESRD cohorts. Finally, preliminary data from a recent pilot study at MGH (NCT01612429) suggests that amino acid supplementation in patients with ESRD undergoing maintenance hemodialysis can attenuate carbamylation of proteins.
The proposed randomized study will directly evaluate the impact of amino acid supplementation on: (1) the burden of carbamylation in terms of %C-Alb; and (2) selected intermediate determinants of clinical outcomes, i.e., markers of inflammation, cardiac stress, and erythropoietin responsiveness.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Amino acid supplementation NephrAmine® | Experimental | Dietary Supplement: Amino acid supplementation NephrAmine®250 mL of 5.4% amino acid solution (NephrAmine) by intravenous infusion 3 x weekly for 8 weeks plus 4 weeks of follow-up. |
| Standard-of-care | No intervention | –Standard-of-care does not include amino acid supplementation, but this control arm will be evaluated for the same outcomes as the experimental arm for 8 weeks plus 4 weeks of follow-up |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Informed of the investigational nature of the study and sign written informed consent
- Willing and able to adhere to all study-related procedures, including adherence to study medication regimen
- ≥18 years old
- On stable medical therapy in the last 30 days before the study entry, defined as no change, addition, or removal of medications
- Patients must satisfy the following criteria based on the initial screening laboratory values:
Key exclusion criteria (11 listed)
- Taking any type of amino acid supplementation within the last 90 days
- Received parenteral nutrition within last 90 days
- History of allergy to any amino acid compound
- Poorly controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 110 mmHg during any of the previous 3 dialysis sessions (confirmed by repeat)
- Severe hepatic impairment
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 |
|---|---|---|
| Amino acid supplementation NephrAmine®Also: NephrAmine®Dialysis patients will be randomized to receive either 250 mL of NephrAmine® (5.4% amino acids for injection; B. Braun Medical, Inc) containing ~14 grams of essential amino acids during each dialysis session (3 times weekly for 8 weeks) or no treatment (standard-of-care) | Dietary supplement | Amino acid supplementation NephrAmine® |
Primary outcome
Differences in plasma carbamylated albumin (C-Alb) levels
Time frame: Baseline and weeks 4, 8, and 12
4 secondary outcomes
Safety of amino acid infusion
Time frame: Baseline and weeks 4, 8, and 12
Differences in cardiac markers
Time frame: Baseline and weeks 4, 8, and 12
Differences in inflammatory markers
Time frame: Baseline and weeks 4, 8, and 12
Differences in erythropoietin resistance
Time frame: Baseline and weeks 4, 8, and 12
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Feb 2021.
- Background: PubMed 25671766Drechsler C, Kalim S, Wenger JB, Suntharalingam P, Hod T, Thadhani RI, Karumanchi SA, Wanner C, Berg AH. Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease. Kidney Int. 2015 Jun;87(6):1201-8. doi: 10.1038/ki.2014.429. Epub 2015 Feb 11.
- Background: PubMed 23970130Kalim S, Tamez H, Wenger J, Ankers E, Trottier CA, Deferio JJ, Berg AH, Karumanchi SA, Thadhani RI. Carbamylation of serum albumin and erythropoietin resistance in end stage kidney disease. Clin J Am Soc Nephrol. 2013 Nov;8(11):1927-34. doi: 10.2215/CJN.04310413. Epub 2013 Aug 22.
- Background: PubMed 23467560Berg AH, Drechsler C, Wenger J, Buccafusca R, Hod T, Kalim S, Ramma W, Parikh SM, Steen H, Friedman DJ, Danziger J, Wanner C, Thadhani R, Karumanchi SA. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci Transl Med. 2013 Mar 6;5(175):175ra29. doi: 10.1126/scitranslmed.3005218.
- Background: PubMed 23431074Koeth RA, Kalantar-Zadeh K, Wang Z, Fu X, Tang WH, Hazen SL. Protein carbamylation predicts mortality in ESRD. J Am Soc Nephrol. 2013 Apr;24(5):853-61. doi: 10.1681/ASN.2012030254. Epub 2013 Feb 21.
- Individual participant dataSharing planned: Undecided
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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. This study is not recruiting at the moment.
Sahir Kalim, MD, MMSc principal investigator
Massachusetts General Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Amino acid supplementation NephrAmine® in people with End Stage Renal Failure on Dialysis, run by Massachusetts General Hospital at 2 sites in United States.
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 12 inclusion and 11 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: finished, as of the sponsor's last update on 24 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Differences in plasma carbamylated albumin (C-Alb) levels (time frame: Baseline and weeks 4, 8, and 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02472834, which also lists 4 linked publications.
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 24 Feb 2021.