SIAD - Syndrome of Inappropriate AntidiuresisUREA-BIVANCT07528365
Urea for Treatment of Hyponatremia in Patients With SIAD Unresponsive to Fluid Restriction
A study testing urea in people with SIAD - Syndrome of Inappropriate Antidiuresis, run by University of Turin, Italy at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- SIAD - Syndrome of Inappropriate Antidiuresis
- What is being tested?
- urea
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteItaly
- Study dates
- 12 Sep 2024to Dec 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
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
- 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
Show all 9Show fewer
- 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
Who cannot join
- 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
Show all 9Show fewer
- Pregnancy or breastfeeding
- Known allergy or intolerance to urea
- Patient refusal or inability to provide written informed consent
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site, 1 recruiting
- Recruiting
AOU Città della Salute e della Scienza
Turin, Piedmont, Italy, 10126
Silvia Grottoli, Professor, +390116337400, silvia.grottoli@unito.it
About this study
Official title: 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.
Read the 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.
- Being tested
- urea
- Keywords
- hyponatremia, urea, plasma sodium level, SIAD
- Medical subject headings
- Inappropriate ADH Syndrome, Hyponatremia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ureaDietary 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.
| Study group | Role | What they receive |
|---|---|---|
| Urea therapy | Experimental | Participants will receive oral urea supplementation for 42±4 days, followed by a 10±2-day washout period Receives: Dietary Supplement: urea |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: 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
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
Measured: Baseline, day 42±4, and 10±2 days post-therapy
Bioimpedance adaptation
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
Measured: Baseline, day 42±4, and 10±2 days post-therapy
Bone turnover markers
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
Measured: Baseline, day 42±4, and 10±2 days post-therapy
Cognitive performance
Changes in Montreal Cognitive Assessment (MoCA) scores from baseline to day 42±4, to evaluate the effect of sodium increase normalization on cognitive function
Measured: Baseline and day 42±4
Variation in other Serum and Urinary Analytes
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
Measured: Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Apr 2026
- Study start12 Sep 2024
- Primary completionNov 2027 (estimated)
- Study completionDec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for SIAD - Syndrome of Inappropriate AntidiuresisStudies of the same condition, open and under way.
- 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Turin, Italy
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07528365
- Sponsor's protocol ID
- UREA-BIVA-01
- Acronym
- UREA-BIVA
- Status last verified
- Apr 2026
- First submitted
- 7 Apr 2026
- Last updated
- 14 Apr 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 30181129Perello-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.
PubMed 35715573Decaux 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.
PubMed 7386514Soupart 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.
PubMed 22403276Woudstra 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.
PubMed 32332187Hammonds 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.
PubMed 35615479Lockett 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.
PubMed 30614552Nervo 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.
PubMed 30868608Chander 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.
PubMed 39362395
Study at a glance
From the registry record, last updated by the sponsor on 14 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy of Oral Urea Supplementation in Patients With SIAD Not Adequately Controlled With Fluid Restriction
- ClinicalTrials.gov ID
- NCT07528365
- Acronym / sponsor ID
- UREA-BIVA / UREA-BIVA-01
- Keywords
- hyponatremia, urea, plasma sodium level, SIAD
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- University of Turin, ItalyUniversity, hospital or other
- Study start
- 12 Sep 2024 (actual)
- Primary completion
- Nov 2027 (estimated)
- Study completion
- Dec 2027 (estimated)
- First posted
- 14 Apr 2026 (actual)
- 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.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Urea therapy | Experimental | Dietary Supplement: ureaParticipants will receive oral urea supplementation for 42±4 days, followed by a 10±2-day washout period |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (9 listed)
- 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
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 |
|---|---|---|
| ureaPatients 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. | Dietary supplement | Urea therapy |
Primary outcome
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)
5 secondary outcomes
Changes in copeptin, NT-proBNP, and MR-proADM levels
Time frame: Baseline, day 42±4, and 10±2 days post-therapy
Bioimpedance adaptation
Time frame: 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
Cognitive performance
Time frame: 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
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Apr 2026.
- Background: PubMed 30181129Rondon-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.
- Background: PubMed 35715573Perello-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.
- Background: PubMed 7386514Decaux 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.
- Background: PubMed 22403276Soupart 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.
- Background: PubMed 32332187Woudstra 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.
- Background: PubMed 35615479Hammonds 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.
- Background: PubMed 30614552Lockett 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.
- Background: PubMed 30868608Nervo 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.
- Background: PubMed 39362395Chander 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.
- Individual participant dataSharing planned: No
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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.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing urea in people with SIAD - Syndrome of Inappropriate Antidiuresis, run by University of Turin, Italy at 1 site in Italy.
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 9 inclusion and 9 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: looking for participants now, as of the sponsor's last update on 14 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in serum sodium levels (time frame: Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation). 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 NCT07528365, which also lists 9 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 14 Apr 2026.