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Trial registered on ANZCTR


Registration number
ACTRN12619001683123p
Ethics application status
Submitted, not yet approved
Date submitted
24/11/2019
Date registered
2/12/2019
Date last updated
2/12/2019
Date data sharing statement initially provided
2/12/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Tolvaptan versus fluid restriction in acutely hospitalised patients with low blood sodium concentration.
Scientific title
Open-label randomised controlled trial of tolvaptan versus fluid restriction in acutely hospitalised patients with euvolaemic or hypervolaemic hyponatraemia.
Secondary ID [1] 299895 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hyponatraemia 315316 0
Condition category
Condition code
Metabolic and Endocrine 313618 313618 0 0
Other endocrine disorders

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

On day one the dose will be 15mg.

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 < 135 mmol/L and the increment over the previous 24h is in the range of 5-8 mmol/L, the dose will be 15mg. If the serum sodium is < 135 mmol/L and the increment over the previous 24h is <5 mmol/L, the dose will be 30mg.

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 < 135 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 < 135 mmol/L and the increment over the previous 24h is <5 mmol/L, the dose on day 3 will be 15mg if 0mg was given on day 2, 30mg if 15mg was given on day 2, or 60mg if 30mg was given on day 2.


Intervention code [1] 316167 0
Treatment: Drugs
Comparator / control treatment
The control treatment is fluid restriction titrated according to the serum sodium response.
Control group
Active

Outcomes
Primary outcome [1] 322065 0
Change in average serum sodium from baseline (day 1 of admission) to day 4 (or day of hospital discharge if that occurs earlier than day 4).
Timepoint [1] 322065 0
Day 4 of admission or day of hospital discharge if earlier than day 4.
Secondary outcome [1] 377181 0
Change in average serum sodium from baseline (day 1 of admission) to day 4 (or day of hospital discharge if that occurs earlier than day 4) in the euvolaemic subgroup.
Timepoint [1] 377181 0
Day 4 (or day of hospital discharge if that occurs earlier than day 4)
Secondary outcome [2] 377182 0
Change in average serum sodium from baseline (day 1 of admission) to day 4 (or day of hospital discharge if that occurs earlier than day 4) in the hypervolaemic subgroup.
Timepoint [2] 377182 0
Day 4 (or day of hospital discharge if that occurs earlier than day 4)
Secondary outcome [3] 377183 0
Serum sodium increment in the first 24 hours
Timepoint [3] 377183 0
Day 2 of admission
Secondary outcome [4] 377184 0
Serum sodium increment in first 48 hours
Timepoint [4] 377184 0
Day 3 of admission
Secondary outcome [5] 377185 0
Proportion of participants normalising serum sodium (serum sodium > 134 mmol/L)
Timepoint [5] 377185 0
Day 4 (or day of discharge if earlier)
Secondary outcome [6] 377186 0
Length of hospital stay calculated from hospital medical record
Timepoint [6] 377186 0
Assessed at study end
Secondary outcome [7] 377187 0
Requirement for rescue with enteral or IV dextrose or water and/or desmopressin obtained from review of the medical record.
Timepoint [7] 377187 0
Day 4 (or day of discharge if earlier)
Secondary outcome [8] 377188 0
Timed up and go test score
Timepoint [8] 377188 0
At 24, 48, 72, and 96 hours (or at discharge if discharged sooner
Secondary outcome [9] 377189 0
Hyponatraemic Symptoms Questionnaire Score
Timepoint [9] 377189 0
At 24, 48, 72, and 96 hours (or at discharge if discharged sooner
Secondary outcome [10] 377190 0
Re-admission rate, obtained from the medical record and/or by asking the participant.
Timepoint [10] 377190 0
34 days after randomisation
Secondary outcome [11] 377191 0
Delirium symptom interview score
Timepoint [11] 377191 0
At 24, 48, 72, and 96 hours (or at discharge if discharged sooner
Secondary outcome [12] 377192 0
Exit questionnaire treatment satisfaction score. This questionnaire has been designed specifically for this study.
Timepoint [12] 377192 0
34 days after randomisation

Eligibility
Key inclusion criteria
Acutely hospitalised patients with hypotonic hyponatraemia (serum sodium 115-130 mmol/L) at 0800 hours on day 1 of their hospital admission (day of presentation being day 0).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Hypovolaemia
Acute polydipsia (urine specific gravity < 1.050)
Severe symptoms warranting hypertonic saline
Thiazide or thiazide-like diuretic use within preceding 5 days
Risk factors for osmotic demyelination syndrome (malnutrition, alcohol abuse, Child-Pugh B or C cirrhosis, potassium < 3.5 mmol/L on day 1, increment in serum sodium from day 0 to day 1 of > 0.5mmol/L/h or > 10 mmol/L).
Glucocorticoid deficiency
Mineralocorticoid deficiency
Overt hypothyroidism
Chronic kidney disease stage 5
Inability to drink fluid orally unaided
Admission diagnosis of pulmonary infection
Pregnancy or breastfeeding
Day 1 venous blood gas glucose > 20 mmol/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 a mean difference between tolvaptan and placebo groups in sodium increment at day 4, of approximately 4 mmol/L. The standard deviation (SD) in day 4 sodium concentrations was approximately 4.9 (effect size 0.8). We determined that 2 mmol/L is the minimally clinically relevant difference between tolvaptan and fluid restriction. Using the same SD, we calculated that 64 participants per group would be required to detect this difference (80% power, 2-sided p-value = 0.05). To allow for drop-outs and autocorrection of hyponatraemia without specific therapy, a total of 166 participants will be recruited (83 per group).

Change in average serum sodium from baseline (Day 1 0600hrs) to Day 4 0600hrs (or day of discharge if earlier) will be compared between treatment groups. Analysis will be by the intention-to-treat principle so that data from participants who withdraw or violate the protocol will be included in their assigned treatment group.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 15289 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 28599 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 304359 0
Commercial sector/Industry
Name [1] 304359 0
Otsuka Australia Pharmaceutical
Address [1] 304359 0
Suite 2.03, Level 2
9 Help St, Chatswood NSW 2067
Country [1] 304359 0
Australia
Funding source category [2] 304360 0
University
Name [2] 304360 0
University of Melbourne
Address [2] 304360 0
Grattan St
Parkville
Victoria 3010
Country [2] 304360 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
Grattan St
Parkville
Victoria 3010
Country
Australia
Secondary sponsor category [1] 304608 0
None
Name [1] 304608 0
Address [1] 304608 0
Country [1] 304608 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 304802 0
Austin Health HREC
Ethics committee address [1] 304802 0
145 Studley Rd
Heidelberg VIC 3084
Ethics committee country [1] 304802 0
Australia
Date submitted for ethics approval [1] 304802 0
19/09/2019
Approval date [1] 304802 0
Ethics approval number [1] 304802 0

Summary
Brief summary
Hyponatraemia is common in hospitalised patients. Our Australian data demonstrate that hyponatraemia leads to adverse outcomes and delays hospital discharge, due to unavailability of effective pathophysiology-based treatment. In Australia, fluid restriction is the mainstay of treatment for euvolaemic and hypervolaemic hypotonic hyponatraemia in hospital inpatients. Tolvaptan, a vasopressin V2-receptor antagonist, may be more effective.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98258 0
Prof Mathis Grossmann
Address 98258 0
Level 7 Lance Townsend Building, Austin Health
145 Studley Road
Heidelberg VIC 3084
Country 98258 0
Australia
Phone 98258 0
+61 3 94965000
Fax 98258 0
Email 98258 0
mathisg@unimelb.edu.au
Contact person for public queries
Name 98259 0
Dr Nicholas Russell
Address 98259 0
Endocrine Department Austin Health
145 Studley Road
Heidelberg VIC 3084
Country 98259 0
Australia
Phone 98259 0
+61 3 94965000
Fax 98259 0
Email 98259 0
nicholas.russell@austin.org.au
Contact person for scientific queries
Name 98260 0
Dr Nicholas Russell
Address 98260 0
Endocrine Department Austin Health
145 Studley Road
Heidelberg VIC 3084
Country 98260 0
Australia
Phone 98260 0
+61 3 94965000
Fax 98260 0
Email 98260 0
nicholas.russell@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 nicholas.russell@austin.org.au)
What supporting documents are/will be available?
No other documents available
Summary results
No Results