- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02472834
Trial of Carbamylation in Renal Disease-Modulation With Amino Acid Therapy (CarRAAT-2)
Amino Acid Therapy to Modify Protein Carbamylation in End Stage Renal Disease: A Randomized Trial
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital
-
Boston, Massachusetts, United States, 02201
- Fresenius Medical Centers (local affilliates)
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 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)
- 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
Exclusion Criteria:
- 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
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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.
|
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)
Other Names:
|
No Intervention: Standard-of-care
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 the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Differences in plasma carbamylated albumin (C-Alb) levels
Time Frame: Baseline and weeks 4, 8, and 12
|
Baseline and weeks 4, 8, and 12
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety of amino acid infusion
Time Frame: Baseline and weeks 4, 8, and 12
|
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
|
Baseline and weeks 4, 8, and 12
|
Differences in cardiac markers
Time Frame: Baseline and weeks 4, 8, and 12
|
Changes in Troponin T and NT-Pro-BNP during 8 weeks of therapy and 4 weeks of follow-up post-therapy
|
Baseline and weeks 4, 8, and 12
|
Differences in inflammatory markers
Time Frame: Baseline and weeks 4, 8, and 12
|
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
|
Baseline and weeks 4, 8, and 12
|
Differences in erythropoietin resistance
Time Frame: Baseline and weeks 4, 8, and 12
|
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
|
Baseline and weeks 4, 8, and 12
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Sahir Kalim, MD, MMSc, Massachusetts General Hospital
Publications and helpful links
General 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.
- Kalim 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.
- Berg 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.
- Koeth 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2015-P-000562
- 5K23DK106479-04 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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.
Clinical Trials on End Stage Renal Failure on Dialysis
-
Peripal AGUniversity Hospital Birmingham NHS Foundation Trust; Swiss Federal Institute...CompletedRenal Failure | Peritoneal Dialysis | Renal Replacement Therapy | End Stage Renal Failure on Dialysis | End Stage Renal Disease on DialysisUnited Kingdom
-
The University of Hong KongBaxter Healthcare CorporationCompleted
-
Massachusetts General HospitalCompletedEnd Stage Renal Failure on DialysisUnited States
-
Universidade Estadual Paulista Júlio de Mesquita...CompletedEnd Stage Renal Failure on Dialysis
-
Palo Alto Veterans Institute for ResearchUnknownEnd Stage Renal Failure on DialysisUnited States
-
Praxisverbund Dialyse und AphereseCompletedEnd Stage Renal Failure on Dialysis
-
Hallym University Medical CenterWithdrawnEnd Stage Renal Failure on DialysisKorea, Republic of
-
Oxford Brookes UniversityOxford University Hospitals NHS TrustCompletedEnd Stage Renal Failure on DialysisUnited Kingdom
-
Merit Medical Systems, Inc.CryoLife, Inc.WithdrawnEnd Stage Renal Failure on DialysisUnited States
-
University Hospital, BonnGerman Sport University, CologneCompletedEnd Stage Renal Failure on DialysisGermany
Clinical Trials on Amino acid supplementation NephrAmine®
-
Massachusetts General HospitalCompletedEnd Stage Renal Failure on DialysisUnited States
-
University of TorontoIovate Health Sciences International IncCompletedExercise | Metabolism | Amino Acids, EssentialCanada
-
University of StellenboschFresenius KabiRecruiting
-
Assistance Publique - Hôpitaux de ParisCompleted
-
CES UniversityNutreva S.A.S.; Foundation Child Care - FANCompleted
-
Massachusetts General HospitalCompletedHereditary Sensory and Autonomic Neuropathy Type IUnited States
-
University of Western Ontario, CanadaUnknownObesity | Weight LossCanada
-
Institut National de la Recherche AgronomiqueAgroParisTechCompleted
-
University of Sao PauloCompleted
-
Shanghai Meiji Health Science and Technology Co...CompletedSports Injury