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Trial registered on ANZCTR

Registration number

ACTRN12619001683123

Ethics application status

Approved

Date submitted

24/11/2019

Date registered

2/12/2019

Date last updated

31/05/2024

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]

Nil Known

Universal Trial Number (UTN)

Trial acronym

TVFR-HypoNa

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Hyponatraemia

Condition category

Condition code

Metabolic and Endocrine

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 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 < 135 mmol/L and the increment over the previous 24h is in the range of 5-8 mmol/L, the dose continue at 7.5mg.
- If the serum sodium is < 135 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 < 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 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.

Intervention code [1]

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]

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]

Day 4 of admission or day of hospital discharge if earlier than day 4.

Secondary outcome [1]

Difference between groups of area under the curve of serial direct serum sodium measurements in mmol/L

Timepoint [1]

Day 4 (or day of hospital discharge if that occurs earlier than day 4)

Secondary outcome [2]

Serum sodium increment in the first 24 hours

Timepoint [2]

Day 2 of admission

Secondary outcome [3]

Serum sodium increment in first 48 hours

Timepoint [3]

Day 3 of admission

Secondary outcome [4]

Proportion of participants normalising serum sodium (serum sodium > 134 mmol/L)

Timepoint [4]

Day 4 (or day of discharge if earlier)

Secondary outcome [5]

Length of hospital stay calculated from hospital medical record

Timepoint [5]

Assessed at study end

Secondary outcome [6]

Requirement for rescue with enteral or IV dextrose or water and/or desmopressin obtained from review of the medical record.

Timepoint [6]

Day 4 (or day of discharge if earlier)

Secondary outcome [7]

Timed up and go test score

Timepoint [7]

At 24, 48, 72, and 96 hours (or at discharge if discharged sooner

Secondary outcome [8]

Hyponatraemic Symptoms Questionnaire Score

Timepoint [8]

At 24, 48, 72, and 96 hours (or at discharge if discharged sooner

Secondary outcome [9]

Re-admission rate, obtained from the medical record and/or by asking the participant.

Timepoint [9]

34 days after randomisation

Secondary outcome [10]

Confusion Assessment Method (CAM-S) Short Form score.

Timepoint [10]

At 24, 48, 72, and 96 hours (or at discharge if discharged sooner

Secondary outcome [11]

Exit questionnaire treatment satisfaction score. This questionnaire has been designed specifically for this study.

Timepoint [11]

34 days after randomisation

Secondary outcome [12]

Plasma sodium concentration 30 days after discharge

Timepoint [12]

30 days after discharge

Secondary outcome [13]

Subgroup analyses according to: volume status (euvolaemic vs hypervolaemic), baseline serum sodium level, baseline urine sodium level, baseline urine osmolality, baseline urine/plasma tonicity ratio.

Timepoint [13]

Day 4 (or Day of discharge if earlier)

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

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Hypovolaemia
Acute polydipsia (urine specific gravity < 1.003)
Severe symptoms warranting hypertonic saline (vomiting, coma (GCS <8), deep somnolence (sedation score >1), seizure, respiratory arrest)
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).
Systolic blood pressure <100mmHg
Glucocorticoid deficiency
Mineralocorticoid deficiency
Overt hypothyroidism
Chronic kidney disease stage 5
Inability to drink fluid unaided
Pregnancy or breastfeeding
Marked hyperglycaemia (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 4 mmol/L is the minimally clinically relevant difference between tolvaptan and fluid restriction. Using the same SD, we calculated that 26 participants per group would be required.

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

Completed

Date of first participant enrolment

Anticipated

21/05/2021

Actual

21/05/2021

Date of last participant enrolment

Anticipated

31/12/2022

Actual

9/04/2024

Date of last data collection

Anticipated

4/02/2023

Actual

12/05/2024

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment postcode(s) [1]

3084 - Heidelberg

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Otsuka Australia Pharmaceutical

Address [1]

Suite 2.03, Level 2
9 Help St, Chatswood NSW 2067

Country [1]

Australia

Funding source category [2]

University

Name [2]

University of Melbourne

Address [2]

Grattan St
Parkville
Victoria 3010

Country [2]

Australia

Primary sponsor type

University

Name

The University of Melbourne

Address

Grattan St
Parkville
Victoria 3010

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health HREC

Ethics committee address [1]

145 Studley Rd
Heidelberg VIC 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

19/09/2019

Approval date [1]

12/02/2020

Ethics approval number [1]

HREC/48055/Austin-2019

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

Prof Mathis Grossmann

Address

Level 7 Lance Townsend Building, Austin Health
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61 3 94965000

Fax

[email protected]

Contact person for public queries

Name

Annabelle Warren

Address

Endocrine Department Austin Health
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61 3 94965000

Fax

[email protected]

Contact person for scientific queries

Name

Nicholas Russell

Address

Endocrine Department Austin Health
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61 3 94965000

Fax

[email protected]

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 [email protected])

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

Source	Title	Year of Publication	DOI
Embase	Tolvaptan versus fluid restriction in acutely hospitalised patients with moderate-profound hyponatraemia (TVFR-HypoNa): design and implementation of an open-label randomised trial.	2022	https://dx.doi.org/10.1186/s13063-022-06237-5

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically