Urea for Treatment of Hyponatremia in Patients With SIAD Unresponsive to Fluid Restriction (UREA-BIVA)

April 7, 2026 updated by: University of Turin, Italy

Efficacy of Oral Urea Supplementation in Patients With SIAD Not Adequately Controlled With Fluid Restriction

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Hyponatremia (serum sodium, s-Na <135 mmol/L) is the most common electrolyte disorder in hospitalized patients, with prevalence increasing with length of hospital stay. Among hypotonic euvolemic hyponatremias, the syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause and is characterized by impaired free water excretion. SIAD may result from central nervous system disorders, pulmonary diseases, malignancies, or medications, and remains a diagnosis of exclusion.

When possible, treating the underlying cause can resolve the syndrome; however, in many cases the cause remains unknown and therapeutic options are limited. First-line treatment is fluid restriction, which is often insufficient and difficult to maintain in the long term. AVP receptor antagonists, such as tolvaptan, are effective but expensive and may carry a risk of overly rapid correction of serum sodium.

Second-line therapy recommended by current guidelines is urea supplementation, which has shown safety and efficacy in normalizing serum sodium. However, most available evidence derives from retrospective studies, and prospective data are limited.

This study aims to evaluate the effectiveness of urea supplementation in patients with chronic, mildly symptomatic SIAD-related hyponatremia not adequately controlled by fluid restriction (≤1500 mL/day), and to explore its effects on neuroendocrine adaptation, body fluid composition, and bone metabolism.

Study Type

Interventional

Enrollment (Estimated)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • Piedmont, Italy
      • Turin, Piedmont, Italy, Italy, 10126
        • Recruiting
        • AOU Città della Salute e della Scienza
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Confirmed diagnosis of SIAD established prior to study inclusion, defined as:
  • 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)

Fulfillment of all diagnostic criteria at baseline (day 0) was not mandatory, as the diagnosis of SIAD had already been established prior to study inclusion based on overall clinical assessment.

- Written informed consent obtained

Exclusion Criteria:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Urea therapy
Participants will receive oral urea supplementation for 42±4 days, followed by a 10±2-day washout period
Dietary supplement: urea

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in serum sodium levels
Time Frame: Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in copeptin, NT-proBNP, and MR-proADM levels
Time Frame: Baseline, day 42±4, and 10±2 days post-therapy
Changes in copeptin, NT-proBNP, and MR-proADM levels from baseline to day 42±4 and after urea discontinuation at 10±2 days, to evaluate chronic neuroendocrine response to urea therapy
Baseline, day 42±4, and 10±2 days post-therapy
Bioimpedance adaptation
Time Frame: Baseline, day 42±4, and 10±2 days post-therapy
Changes in intra- and extracellular fluid volumes as assessed by bioimpedance vector analysis (BIVA) from baseline to day 42±4 and after urea discontinuation at 10±2 days
Baseline, day 42±4, and 10±2 days post-therapy
Bone turnover markers
Time Frame: Baseline, day 42±4, and 10±2 days post-therapy
Changes in serum C-terminal telopeptide (CTX) and N-terminal pro-peptide of type 1 collagen (PINP) from baseline to day 42±4 and after urea discontinuation at 10±2 days, to evaluate bone metabolism response to variation of serum sodium levels
Baseline, day 42±4, and 10±2 days post-therapy
Cognitive performance
Time Frame: Baseline and day 42±4
Changes in Montreal Cognitive Assessment (MoCA) scores from baseline to day 42±4, to evaluate the effect of sodium increase normalization on cognitive function
Baseline and day 42±4
Variation in other Serum and Urinary Analytes
Time Frame: Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation
Blood (potassium, creatinine, urea, uric acid, glucose, plasma osmolality) and urine analytes (potassium, creatinine, urea, uric acid, urine osmolality, and fractional excretion of sodium, potassium, urea, and uric acid) will be assessed at baseline, day 1, day 21±4, day 42±4, and 10±2 days post-therapy to evaluate changes following initiation and discontinuation of urea supplementation, and to explore potential predictors of treatment response and remission of hyponatremia
Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Turin, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 12, 2024

Primary Completion (Estimated)

November 1, 2027

Study Completion (Estimated)

December 1, 2027

Study Registration Dates

First Submitted

April 7, 2026

First Submitted That Met QC Criteria

April 7, 2026

First Posted (Actual)

April 14, 2026

Study Record Updates

Last Update Posted (Actual)

April 14, 2026

Last Update Submitted That Met QC Criteria

April 7, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UREA-BIVA-01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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.

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