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Trial registered on ANZCTR


Registration number
ACTRN12624000756527p
Ethics application status
Not yet submitted
Date submitted
29/05/2024
Date registered
20/06/2024
Date last updated
20/06/2024
Date data sharing statement initially provided
20/06/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Tolvaptan versus Urea in acutely hospitalised patients with low blood sodium concentration
Scientific title
A randomised multi-centre trial of Tolvaptan vs. Urea for therapy of hyponatraemia after failure of fluid restriction in hospital inpatients
Secondary ID [1] 312248 0
Nil known
Universal Trial Number (UTN)
Trial acronym
TVU Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hyponatraemia 333955 0
Condition category
Condition code
Metabolic and Endocrine 330628 330628 0 0
Other endocrine disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Tolvaptan
Tolvaptan will be administered once daily for 3 days in oral tablet form.

On day one the dose will be 7.5mg.

On day 2 the dose will be titrated according to serum sodium and the serum sodium increment over the previous 24 hours.
- If the serum sodium is > 134 mmol/L the dose will be 0mg.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is >8 mmol/L the dose will be 0mg.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is in the range of 5-8 mmol/L, the dose will continue at 7.5mg.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is <5 mmol/L, the dose will be increased to 15mg.

On day 3 the dose will be titrated according to serum sodium, the serum sodium increment, over the previous 24 hours, and the dose received on day 2.
- If the serum sodium is > 134 mmol/L the dose will be 0mg.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is >8 mmol/L the dose will be 0mg.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is in the range of 5-8 mmol/L, the same dose will be given on day 3 as was given on day 2.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is <5 mmol/L, the dose on day 3 will be increased: 7.5mg if 0mg was given on day 2, 15mg if 7.5mg was given on day 2, or 30mg if 15mg was given on day 2.

Tolvaptan will be administered by the ward nursing staff, together with their regular medications (if any). The ward nursing staff will supervise the patient while they are swallowing the tablets, which is in keeping with standard hospital protocol.
Intervention code [1] 328699 0
Treatment: Drugs
Comparator / control treatment
Arm 2: Urea
Urea will be administered once daily for 3 days in oral powder form, dissolved in 100mL of cordial or juice. Urea will be administered in conjunction with an oral fluid restriction of 1000mL per day.

On day one the dose will be 30g.

On day 2 the dose will be titrated according to serum sodium and the serum sodium increment over the previous 24 hours.
- If the serum sodium is > 134 mmol/L the dose will be 0mg.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is >8 mmol/L, the dose will be 0mg.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is in the range of 5-8 mmol/L, the dose will continue at 30g.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is <5 mmol/L, the dose will be increased to 30g mane, 15g nocte (45g per day).

On day 3 the dose will be titrated according to serum sodium, the serum sodium increment, over the previous 24 hours, and the dose received on day 2.
- If the serum sodium is > 134 mmol/L the dose will be 0mg.
- If the serum sodium if less than or equal to 134 mmol/L and the increment over the previous 24h is >8 mmol/L the dose will be 0mg.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is in the range of 5-8 mmol/L, the same dose will be given on day 3 as was given on day 2.
- If the serum sodium is less than or equal to 134 mmol/L and the increment over the previous 24h is <5 mmol/L, the dose on day 3 will be increased: 30g if 0mg was given on day 2, 45g (30g mane, 15g nocte) if 30g was given on day 2, or 60g (30g twice daily) if 45g was given on day 2.

Urea will be administered by the ward nursing staff. The ward nursing staff will prepare the urea by dissolving it in 100mL of cordial or juice, and supervise the patient while they are swallowing the urea-containing drink. This is in keeping with standard hospital protocol for any medications that are dissolved in fluid.
Control group
Active

Outcomes
Primary outcome [1] 338372 0
Change in serum sodium over time, from baseline (admission day 1) to admission day 4 (or day of discharge if discharge occurs earlier than day 4).
Timepoint [1] 338372 0
Day 4 of admission or day of hospital discharge if earlier than day 4.
Secondary outcome [1] 435657 0
Serum sodium increment in the first 24 hours
Timepoint [1] 435657 0
Day 2 of admission
Secondary outcome [2] 435658 0
Serum sodium increment in the first 48 hours
Timepoint [2] 435658 0
Day 3 of admission
Secondary outcome [3] 435659 0
Proportion of participants normalising serum sodium (serum sodium > 134 mmol/L)
Timepoint [3] 435659 0
Day 4 (or day of discharge if earlier)
Secondary outcome [4] 435660 0
Length of hospital stay calculated from hospital medical record
Timepoint [4] 435660 0
Assessed at study end
Secondary outcome [5] 435661 0
Requirement for rescue with enteral or IV dextrose or water and/or desmopressin
Timepoint [5] 435661 0
Day 4 (or day of discharge if earlier)
Secondary outcome [6] 435662 0
Confusion Assessment Method (CAM-S) Short Form score
Timepoint [6] 435662 0
Day 1 and Day 4 (or at discharge if discharged sooner)
Secondary outcome [7] 435663 0
Hyponatraemia Symptom Score
Timepoint [7] 435663 0
Day 1 and Day 4 (or at discharge if discharged sooner)
Secondary outcome [8] 435664 0
Overall health state
Timepoint [8] 435664 0
Day 1 and Day 4 (or at discharge if discharged sooner)
Secondary outcome [9] 435665 0
30 day re-admission rate
Timepoint [9] 435665 0
34 days after randomisation
Secondary outcome [10] 435666 0
Plasma sodium concentration 30 days after discharge
Timepoint [10] 435666 0
30 days after discharge

Eligibility
Key inclusion criteria
Acutely hospitalised patients with hypotonic hyponatraemia (serum sodium 115-130 mmol/L) with sodium rise less than or equal to 4 mmol/L per 24 hours at 0800 hours on day 1 of their hospital admission (day of presentation being day 0), despite at least 24 hours of fluid restriction.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Hypovolaemia defined as either clinical impression of hypovolaemia; or urine sodium <20 mmol/L
Acute polydipsia defined by first collected urine sample specific gravity <1.003
- Severe symptoms warranting hypertonic saline: repeated vomiting on Day 1 of admission, coma (defined by Glasgow Coma Score <8) on Day 1 of admission, deep somnolence (defined by sedation score>1) on Day 1 of admission, seizure at any time during admission, respiratory arrest at any time during admission
- Thiazide or thiazide-like diuretic use within the preceding 5 days
- Risk factors for osmotic demyelination syndrome: malnutrition (BMI <16 or other clinical concern), alcohol abuse (>14 standard drinks per week), child-Pugh B or C cirrhosis, hypokalaemia (K<3.0 mmol/L on Day 1 of admission), increment in serum sodium from baseline to Day 1 of >5mmol/L
- Other endocrine causes of hyponatraemia: untreated glucocorticoid deficiency or mineralocorticoid deficiency, overt hypothyroidism (thyroid stimulating hormone >20)
- Chronic Kidney Disease Stage 5
- Systolic blood pressure <100mmHg
- Inability to drink fluid orally unaided
- Pregnancy (by history, confirmed if necessary by serum beta-hCG) or breastfeeding
- Extreme hyperglycaemia (Day 1 venous blood gas glucose >20mmol/L)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation by an Austin Health staff member at another campus with no substantive involvement in the trial except for guardianship of the pre-generated computer randomisation sequences which are concealed from study personnel for the duration of the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using computer generated randomisation sequences
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The SALT-1 trial reported that tolvaptan resulted in a sodium increment of approximately 4 mmol/L (SD 4.9) more than placebo at Day 4. It was determined that 2 mmol/L is the minimum clinically significant difference in sodium increment between tolvaptan and urea. For a power of 80% and two-sided p-value 0.05, we calculated sample sizes required to detect a 2, 3 or 4 mmol/L difference in serum sodium. We will aim to detect a difference of 3 mmol/L. Allowing a 30% margin for drop-outs and autocorrection of hyponatraemia without specific therapy, a total of 112 participants will be recruited (56 per group).

Change in mean corrected serum sodium from baseline to Day 4 (or discharge if earlier) will be compared between treatment groups. A mixed-effects model based on restricted maximum likelihood (REML) will be used to account for both within-subject variation over time and between-subject variation to assess the treatment effect. Analysis will be performed according to the intention-to-treat principle.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/02/2025
Actual
Date of last participant enrolment
Anticipated
31/12/2026
Actual
Date of last data collection
Anticipated
8/02/2027
Actual
Sample size
Target
112
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26612 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 42653 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 316626 0
University
Name [1] 316626 0
University of Melbourne
Country [1] 316626 0
Australia
Funding source category [2] 316629 0
Commercial sector/Industry
Name [2] 316629 0
Otsuka Australia Pharmaceutical
Country [2] 316629 0
Australia
Primary sponsor type
University
Name
University of Melbourne
Address
Country
Australia
Secondary sponsor category [1] 318811 0
None
Name [1] 318811 0
Address [1] 318811 0
Country [1] 318811 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 315409 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 315409 0
Ethics committee country [1] 315409 0
Australia
Date submitted for ethics approval [1] 315409 0
02/09/2024
Approval date [1] 315409 0
Ethics approval number [1] 315409 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134618 0
Prof Mathis Grossmann
Address 134618 0
Endocrine Department Austin Health, 145 Studley Road, Heidelberg, VIC, 3084
Country 134618 0
Australia
Phone 134618 0
+61 3 9496 5138
Fax 134618 0
Email 134618 0
mathisg@unimelb.edu.au
Contact person for public queries
Name 134619 0
Dr Rose Lin
Address 134619 0
Endocrine Department Austin Health, 145 Studley Road, Heidelberg, VIC, 3084
Country 134619 0
Australia
Phone 134619 0
+61 3 9496 5000
Fax 134619 0
Email 134619 0
rose.lin@austin.org.au
Contact person for scientific queries
Name 134620 0
Dr Annabelle Warren
Address 134620 0
Endocrine Department Austin Health, 145 Studley Road, Heidelberg, VIC, 3084
Country 134620 0
Australia
Phone 134620 0
+61 3 9496 5000
Fax 134620 0
Email 134620 0
annabelle.warren@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results after de-identification
When will data be available (start and end dates)?
Immediately following publication, no end date determined
Available to whom?
Case-by-case basis at the discretion of principal investigator
Available for what types of analyses?
For meta-analysis and other scientifically valid purposes on a case-by-case basis at the discretion of the principal investigator
How or where can data be obtained?
Access subject to approvals by research team (contact annabelle.warren@austin.org.au)


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.