Trial Review

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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] 312071 0
Nil known
Universal Trial Number (UTN)
Trial acronym
FANTrial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
congenital heart disease 333694 0
Single Ventricle 333695 0
Fontan Associated Nephropathy 333696 0
Condition category
Condition code
Cardiovascular 330374 330374 0 0
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] 328512 0
Treatment: Drugs
Comparator / control treatment
Group A (experimental arm) will receive perindopril erbumine, an ACE inhibitor.
Control group
Active

Outcomes
Primary outcome [1] 338140 0
The primary outcome measure is urine albumin-creatinine ratio at 6 months following initiation of treatment.
Timepoint [1] 338140 0
6 months post treatment initiation.
Secondary outcome [1] 434667 0
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] 434667 0
at 6 & 12 months post treatment initiation.
Secondary outcome [2] 435061 0
Hospitalization
Timepoint [2] 435061 0
As per notification
Secondary outcome [3] 435062 0
Arrythmia
Timepoint [3] 435062 0
at any time point
Secondary outcome [4] 435063 0
Heart failure
Timepoint [4] 435063 0
at any time point throughout duration
Secondary outcome [5] 435064 0
Death
Timepoint [5] 435064 0
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?
No
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
50
Accrual to date
Final
Recruitment outside Australia
Country [1] 26290 0
New Zealand
State/province [1] 26290 0

Funding & Sponsors
Funding source category [1] 316431 0
Charities/Societies/Foundations
Name [1] 316431 0
Australian Heart Foundation
Country [1] 316431 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Australian Heart Foundation
Address
Country
Australia
Secondary sponsor category [1] 318599 0
Charities/Societies/Foundations
Name [1] 318599 0
Australian Heart Foundation
Address [1] 318599 0
Country [1] 318599 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 315223 0
Auckland Health Research Ethics Committee
Ethics committee address [1] 315223 0
https://www.auckland.ac.nz/en/research/about-our-research/human-ethics.html
Ethics committee country [1] 315223 0
New Zealand
Date submitted for ethics approval [1] 315223 0
03/05/2024
Approval date [1] 315223 0
Ethics approval number [1] 315223 0

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 134038 0
Dr Ajay Iyengar
Address 134038 0
Starship Hospital: Park Road, Grafton | Private Bag 92024, Auckland 1142
Country 134038 0
New Zealand
Phone 134038 0
+643074949
Fax 134038 0
Email 134038 0
ajayi@adhb.govt.nz
Contact person for public queries
Name 134039 0
Ngaire Polwart
Address 134039 0
Starship Hospital: Park Road, Grafton | Private Bag 92024, Auckland 1142
Country 134039 0
New Zealand
Phone 134039 0
+643074949
Fax 134039 0
Email 134039 0
npolwart@adhb.govt.nz
Contact person for scientific queries
Name 134040 0
Ngaire Polwart
Address 134040 0
Starship: Park Road, Grafton | Private Bag 92024, Auckland 1142
Country 134040 0
New Zealand
Phone 134040 0
+643074949
Fax 134040 0
Email 134040 0
npolwart@adhb.govt.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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.TypeCitationLinkEmailOther DetailsAttachment
22319Ethical approval  npolwart@adhb.govt.nz



Results publications and other study-related documents

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

Documents added automatically
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