ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12624000648527p

Ethics application status

Submitted, not yet approved

Date submitted

2/05/2024

Date registered

21/05/2024

Date last updated

21/05/2024

Date data sharing statement initially provided

21/05/2024

Type of registration

Prospectively registered

Titles & IDs

Public title

FAN Trial: A randomised controlled open label trial assessing the effect of perindopril erbumine on Fontan-Associated Nephropathy

Scientific title

FAN Trial: A randomised controlled open label trial assessing the effect of perindopril erbumine on Fontan-Associated Nephropathy in adults and children 5 years or older.

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

FANTrial

Linked study record

Health condition

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

congenital heart disease

Single Ventricle

Fontan Associated Nephropathy

Condition category

Condition code

Cardiovascular

Other cardiovascular diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a prospective, multi-centre, randomised-controlled trial of perindopril erbumine versus non-intervention in children and adults with a Fontan circulation and evidence of established nephropathy defined as an elevated urine albumin-creatinine ratio (>2.5mg/mmol in males and >3.5mg/mmol in females), and/or a reduced GFR (<90ml/min/1.73m2). Eligible participants will be randomised to receive either perindopril erbumine or no intervention, with stratification based on sex and age (<18 or >=18).
Dosage and route of administration
Group A will receive the ACE inhibitor perindopril erbumine taken orally at the following doses:
<25kg– oral tablet 1mg once daily, titrated to a maximum dose of 2mg once daily
=/>25kg – oral tablet 2mg once daily titrated to a maximum dose of 4mg once daily
Dose tolerance will be checked at visit 2 (2 weeks) and up-titrated only if study investigators are confident that the participant is not experiencing any significant adverse effects. Participants will not be titrating the dose themselves.

Titration for those <25kg will be as follows: commence on 1mg once daily, then increase as tolerated to 2mg at the 2-week visit.

Titration for those =25kg will be as follows: commence on 2mg once daily, then increase as tolerated to 4mg at the 2-week visit.

Participants will then continue on the maximum tolerated dose for a total of 26 weeks, i.e., from week 2 to week 28 post-randomisation. Participants who do not tolerate a total daily dose of 2mg or greater (1mg in those <25 kg) will be excluded from the study.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Group A (experimental arm) will receive perindopril erbumine, an ACE inhibitor.

Control group

Active

Outcomes

Primary outcome [1]

The primary outcome measure is urine albumin-creatinine ratio at 6 months following initiation of treatment.

Timepoint [1]

6 months post treatment initiation.

Secondary outcome [1]

The secondary outcome measures are: glomerular filtration rate (GFR) estimation using serum creatinine and cystatin C based equations at 6 months following initiation of treatment;

Timepoint [1]

at 6 & 12 months post treatment initiation.

Secondary outcome [2]

Hospitalization

Timepoint [2]

As per notification

Secondary outcome [3]

Arrythmia

Timepoint [3]

at any time point

Secondary outcome [4]

Heart failure

Timepoint [4]

at any time point throughout duration

Secondary outcome [5]

Death

Timepoint [5]

at any time point throughout study

Eligibility

Key inclusion criteria

• Are a minimum 5 years of age at the time of screening AND are a minimum of 12-months post Fontan completion (no maximum age)
• Live within Auckland or within 2-3 hour drive of Auckland, NZ or in New South Wales, Australia and can attend multiple study visits at the closest respective centre.
• Are not currently taking an ACE inhibitor or ARB, nor have taken a medication belonging to either of these two classes for greater than 7 consecutive days within the last 3 months prior to screening urine sample.
• Evidence of established nephropathy defined as an elevated urine albumin-creatinine ratio (>2.5mg/mmol in males and >3.5mg/mmol in females) and/or GFR 30-90 ml/min/1.73m2
• Are up-to-date with vaccinations based on the countrywide, accepted schedule of childhood vaccines, including Covid-19 prevention

Minimum age

5 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• Currently pregnant or have been pregnant within the past 12 months beyond the first trimester (13 weeks), (identified at initial phone call).
• Of child-bearing potential with ineffective contraception.
• Currently breastfeeding.
• Known hypersensitivity or intolerance to ACE inhibitors
• Currently on lithium or requiring high doses of diuretics
• eGFR or GFR <30 ml/min/1.73m2 (pre-existing, or identified at baseline)
• Known bilateral renal artery stenosis
• Known uncontrolled hypertension
• Moderate or greater systemic ventricular dysfunction on most recent echocardiogram
• Baseline hyperkalaemia (K > 5.5mmol/L in a non-haemolysed sample)
• Current treatments with regular non-steroidal anti-inflammatory drugs (NSAIDs) (excluding low dose aspirin which is standard of care in many Fontan patients)
• Diagnosis of diabetes mellitus
• Concurrent use of another experimental drug
• Participants who currently require surgical intervention or are anticipated to require surgical intervention relating to their Fontan circulation during the time period of the study.
• Children unable to swallow tablets

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

sealed envelopes

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Simple randomisation using a randomisation table created by computer software

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 4

Type of endpoint/s

Statistical methods / analysis

Because the distribution of ACR exhibit a right skewness, the sample size was performed on the natural logarithmic transformation of ACR. Based on results from a screening study of 150 participants undertaken by the Registry, and after removing outliers and selecting those with elevated urine albumin: creatinine ratio (ACR, >2.5mg/mmol in males or >3.5mg/mmol in females) (primary outcome measure), the mean ACR was 5.7 (1.74 on the log scale, SD on log scale 0.5). To detect a mean reduction in ACR of 30% (log scale difference 0.3542 based on a change of 5.7mg/mmol at baseline to 4 mg/mmol at 6 months) with perindopril erbumine therapy, with a two-sided significance level of 0.05 and power of 80%, 25 participants in each group (control and treatment) are estimated to be needed, allowing for a non-compliance adjustment of 10%.
The target sample size is 74 participants recruited from Auckland and Sydney through the ANZ Fontan Registry.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/06/2024

Actual

Date of last participant enrolment

Anticipated

4/01/2025

Actual

Date of last data collection

Anticipated

1/02/2026

Actual

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Australian Heart Foundation

Address [1]

Country [1]

Australia

Primary sponsor type

Charities/Societies/Foundations

Name

Australian Heart Foundation

Address

Country

Australia

Secondary sponsor category [1]

Charities/Societies/Foundations

Name [1]

Australian Heart Foundation

Address [1]

Country [1]

Australia

Ethics approval

Ethics application status

Submitted, not yet approved

Ethics committee name [1]

Auckland Health Research Ethics Committee

Ethics committee address [1]

https://www.auckland.ac.nz/en/research/about-our-research/human-ethics.html

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

03/05/2024

Approval date [1]

Ethics approval number [1]

Summary

Brief summary

To evaluate in patients with a Fontan circulation with evidence of nephropathy whether initiation of perindopril erbumine reduces the degree of microalbuminuria compared to controls as measured by a spot urine albumin-creatinine ratio over 6 months of treatment.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Ajay Iyengar

Address

Starship Hospital: Park Road, Grafton | Private Bag 92024, Auckland 1142

Country

New Zealand

Phone

+643074949

Fax

[email protected]

Contact person for public queries

Name

Ngaire Polwart

Address

Starship Hospital: Park Road, Grafton | Private Bag 92024, Auckland 1142

Country

New Zealand

Phone

+643074949

Fax

[email protected]

Contact person for scientific queries

Name

Ngaire Polwart

Address

Starship: Park Road, Grafton | Private Bag 92024, Auckland 1142

Country

New Zealand

Phone

+643074949

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

. The study protocol, documentation, data and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorised third party, without prior written approval of the sponsoring institution. Authorised representatives of the sponsoring institution may inspect all documents and records required to be maintained by the Investigator, including but not limited to, medical records (office, clinic or hospital) and pharmacy records for the participants in this study.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
22319	Ethical approval			[email protected]

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.

Trial Review

Documents added manually

Documents added automatically