Trial of Carbamylation in Renal Disease-Modulation With Amino Acid Therapy

NCT02472834 | Completed DMC

• 2 other identifiers: 2015-P-0005625K23DK106479-04
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 2

Brief 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. 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.

Conditions

End Stage Renal Failure on Dialysis

Keywords

Carbamylation; Albumin; Protein structure; Kidney disease

Outcome Measures

Primary Outcomes (1)

• Differences in plasma carbamylated albumin (C-Alb) levels

  Baseline and weeks 4, 8, and 12

Secondary Outcomes (4)

• Safety of amino acid infusion

  Baseline and weeks 4, 8, and 12

• Differences in cardiac markers

  Baseline and weeks 4, 8, and 12

• Differences in inflammatory markers

  Baseline and weeks 4, 8, and 12

• Differences in erythropoietin resistance

  Baseline and weeks 4, 8, and 12

Study Arms (2)

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.

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

Interventions

Amino acid supplementation NephrAmine® DIETARY_SUPPLEMENT

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)

Also known as: NephrAmine®

Amino acid supplementation NephrAmine®

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Fresenius Medical Centers (local affilliates)

Boston, Massachusetts, 02201, United States

Location

Related Publications (4)

• 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.

  PMID: 25671766 BACKGROUND

• 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.

  PMID: 23970130 BACKGROUND

• 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.

  PMID: 23467560 BACKGROUND

• 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.

  PMID: 23431074 BACKGROUND

MeSH Terms

Conditions

Kidney Diseases

Interventions

Amino Acids, Essential

Condition Hierarchy (Ancestors)

Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Sahir Kalim, MD, MMSc

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor in Medicine, Harvard Medical School

Study Record Dates

• First Submitted: June 9, 2015
• First Posted: June 16, 2015
• Study Start: February 1, 2016
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2020
• Last Updated: February 24, 2021

Record last verified: 2021-02

Locations

US (2)