Urea for Treatment of Hyponatremia in Patients With SIAD Unresponsive to Fluid Restriction

NCT07528365 | Recruiting

• 1 other identifier: UREA-BIVA-01
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Hyponatremia due to SIAD is frequently insufficiently corrected by fluid restriction alone, which remains the first-line therapy but is often poorly tolerated. Urea supplementation is recommended as second-line therapy. This prospective study evaluates the effectiveness of oral urea supplementation in patients with chronic SIAD and persistent hyponatremia despite fluid restriction.

Conditions

SIAD - Syndrome of Inappropriate Antidiuresis

Keywords

hyponatremia; urea; plasma sodium level; SIAD

Outcome Measures

Primary Outcomes (1)

• Change in serum sodium levels

  Change in serum sodium from baseline to assess the acute and chronic effectiveness of urea therapy in outpatients with SIAD not adequately compensated by fluid restriction (≤1500 mL/day)

  Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation

Secondary Outcomes (5)

• Changes in copeptin, NT-proBNP, and MR-proADM levels

  Baseline, day 42±4, and 10±2 days post-therapy

• Bioimpedance adaptation

  Baseline, day 42±4, and 10±2 days post-therapy

• Bone turnover markers

  Baseline, day 42±4, and 10±2 days post-therapy

• Cognitive performance

  Baseline and day 42±4

• Variation in other Serum and Urinary Analytes

  Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation

Study Arms (1)

Urea therapy

EXPERIMENTAL

Participants will receive oral urea supplementation for 42±4 days, followed by a 10±2-day washout period

Dietary Supplement: urea

Interventions

urea DIETARY_SUPPLEMENT

Patients with persistent hyponatremia (sodium corrected for glucose \<135 mmol/L) after ≥1 week of fluid restriction (≤1500 mL/day) will receive urea 30 g/day (2 sachets; 1 in the morning and 1 in the evening) dissolved in water, while maintaining fluid restriction ≤1500 mL/day. Blood and urine evaluations will be performed at day 1, day 21±4 and day 42±4, with additional assessments (Montreal Cognitive Assessment \[MoCA\] questionnaire and bioelectrical impedance vector analysis \[BIVA\]) at selected visits. Urea dose adjustments will be based on serum sodium at day 21±4: 45 g/day if Na 130-134 mmol/L, or 60 g/day if Na \<130 mmol/L (maximum 60 g/day). In case of intolerance, the dose will be reduced by one sachet from the planned dose. After day 42±4, urea will be discontinued. A final evaluation will be performed 10±2 days after discontinuation.

Urea therapy

Eligibility Criteria

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

You may qualify if:

• Plasma sodium concentration \<135 mmol/L
• Plasma osmolality \<300 mOsm/kg
• Urine osmolality \>100 mOsm/kg
• Urine sodium concentration \>30 mmol/L
• Intact adrenal and thyroidal function and no use of diuretics in the last 4 weeks
• Clinical euvolemia, defined as an absence of signs of hypovolemia (orthostasis, tachycardia, decreased skin turgor, dry mucous membranes) or hypervolemia (edema, ascites)
• \- Written informed consent obtained

You may not qualify if:

• Chronic hypotonic hyponatremia secondary to another etiology
• Presence of moderate to severe symptoms attributable to plasma hypotonicity
• Severe hypotonic hyponatremia (serum sodium \<120 mmol/L)
• Another ongoing drug treatment for hyponatremia (including vaptans and salt tablets)
• Severe hepatic insufficiency
• eGFR \<45 mL/min/1.73 m²
• Pregnancy or breastfeeding
• Known allergy or intolerance to urea
• Patient refusal or inability to provide written informed consent

Sponsors & Collaborators

• University of Turin, Italy: lead

Study Sites (1)

AOU Città della Salute e della Scienza

Turin, Piedmont, Italy, 10126, Italy

RECRUITING

Related Publications (9)

• Rondon-Berrios H, Tandukar S, Mor MK, Ray EC, Bender FH, Kleyman TR, Weisbord SD. Urea for the Treatment of Hyponatremia. Clin J Am Soc Nephrol. 2018 Nov 7;13(11):1627-1632. doi: 10.2215/CJN.04020318. Epub 2018 Sep 4.

  PMID: 30181129 BACKGROUND

• Perello-Camacho E, Pomares-Gomez FJ, Lopez-Penabad L, Mirete-Lopez RM, Pinedo-Esteban MR, Dominguez-Escribano JR. Clinical efficacy of urea treatment in syndrome of inappropriate antidiuretic hormone secretion. Sci Rep. 2022 Jun 17;12(1):10266. doi: 10.1038/s41598-022-14387-4.

  PMID: 35715573 BACKGROUND

• Decaux G, Brimioulle S, Genette F, Mockel J. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med. 1980 Jul;69(1):99-106. doi: 10.1016/0002-9343(80)90506-9.

  PMID: 7386514 BACKGROUND

• Soupart A, Coffernils M, Couturier B, Gankam-Kengne F, Decaux G. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol. 2012 May;7(5):742-7. doi: 10.2215/CJN.06990711. Epub 2012 Mar 8.

  PMID: 22403276 BACKGROUND

• Woudstra J, de Boer MP, Hempenius L, van Roon EN. Urea for hyponatraemia due to the syndrome of inappropriate antidiuretic hormone secretion. Neth J Med. 2020 Apr;78(3):125-131.

  PMID: 32332187 BACKGROUND

• Hammonds WM, Keating EA, Smetana ME, Smetana KS, Bond MM. Safety and Efficacy of Urea for Hyponatremia. Hosp Pharm. 2022 Jun;57(3):365-369. doi: 10.1177/00185787211037548. Epub 2021 Aug 5.

  PMID: 35615479 BACKGROUND

• Lockett J, Berkman KE, Dimeski G, Russell AW, Inder WJ. Urea treatment in fluid restriction-refractory hyponatraemia. Clin Endocrinol (Oxf). 2019 Apr;90(4):630-636. doi: 10.1111/cen.13930. Epub 2019 Jan 25.

  PMID: 30614552 BACKGROUND

• Nervo A, D'Angelo V, Rosso D, Castellana E, Cattel F, Arvat E, Grossi E. Urea in cancer patients with chronic SIAD-induced hyponatremia: Old drug, new evidence. Clin Endocrinol (Oxf). 2019 Jun;90(6):842-848. doi: 10.1111/cen.13966. Epub 2019 Mar 29.

  PMID: 30868608 BACKGROUND

• Chander S, Kumari R, Lohana AC, Rahaman Z, Parkash O, Shiwlani S, Mohammed YN, Wang HY, Chi H, Tan W, Kumar SK, Sindhu F. Urea to Treat Hyponatremia Due to Syndrome of Inappropriate Antidiuretic Hormone Secretion: A Systematic Review and Meta-Analysis. Am J Kidney Dis. 2025 Mar;85(3):303-319. doi: 10.1053/j.ajkd.2024.07.011. Epub 2024 Oct 1.

  PMID: 39362395 BACKGROUND

MeSH Terms

Conditions

Inappropriate ADH Syndrome; Hyponatremia

Interventions

Urea

Condition Hierarchy (Ancestors)

Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Water-Electrolyte Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Amides; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2026
• First Posted: April 14, 2026
• Study Start: September 12, 2024
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: April 14, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)