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Trial registered on ANZCTR


Registration number
ACTRN12618001124224p
Ethics application status
Submitted, not yet approved
Date submitted
20/06/2018
Date registered
9/07/2018
Date last updated
9/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
FAN Trial: A randomised-controlled trial assessing the effect of lisinopril on Fontan-Associated Nephropathy
Scientific title
FAN Trial: A randomised-controlled trial assessing the effect of lisinopril on Fontan-Associated Nephropathy
Secondary ID [1] 291682 0
None
Universal Trial Number (UTN)
U1111-1215-0721
Trial acronym
FAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Congenital heart defect 308128 0
Nephropathy 308129 0
Condition category
Condition code
Surgery 307165 307165 0 0
Other surgery
Renal and Urogenital 307166 307166 0 0
Kidney disease
Cardiovascular 307617 307617 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is a once daily dose of lisinopril taken orally for 6 months. All doses greater than 5mg will be in tablet form. However, due to the inability to split tablets, all doses less than 5mg will be administered via dispersion of tablets in a small volume of water (lisinopril is very water soluble).
The intervention group will receive lisinopril (APO-lisinopril) at the following doses:
• less than 25kg– oral 0.1mg/kg (max 2.5mg) once daily, titrated to a maximum dose of 0.6mg/kg once daily (doses rounded to nearest 0.5mg)
Titration for those who weigh less than 25kg will be as follows: commence on 0.1mg/kg once daily, then increase as tolerated to 0.2mg/kg at the 2-week visit, 0.4mg/kg at 4 weeks (phone call), and 0.6mg/kg at the 6-week visit. All doses will be rounded to the nearest 0.5mg.
• greater than or equal to 25kg – oral 2.5mg once daily, titrated to a maximum dose of 20mg once daily.
Titration for those who weigh greater than or equal to 25kg will be as follows: commence on 2.5mg once daily, then increase as tolerated to 5mg at the 2-week visit, 10mg at 4 weeks (phone call), and 20mg at the 6-week visit.

Up-titration will take place over a 6-week period, with patients settling on either the maximum allocated dose or the maximum tolerated dose. Patients will attend a study visit at 2 and 6 weeks. Upward titration at 4 weeks will be conducted via a phone call where patients will be asked about potential side effects of the drug. Dose increase will be made only if study investigators are confident that the patient is not experiencing any significant adverse effects.

Patients will then continue on the maximal tolerated dose for a total of 6 months (26 weeks), i.e. from week 6 to week 32. Patients who do not tolerate a total daily dose of 5mg or greater will be excluded from the study.

Drug adherence will be measured by a tablet count at each visit. Participants who take greater than or equal to 75% of their pills will be considered to have been compliant and will be included in the final analysis. Participants will also receive a call at 2 and 4 months post randomisation to check medication compliance.
Intervention code [1] 301405 0
Treatment: Drugs
Comparator / control treatment
The control treatment is a once daily dose of a placebo medication taken orally for 6 months. The placebo is identical in appearance to the treatment medication and will be given in the same dose, duration and mode. The composition of the placebo closely matches the treatment medication and is as follows: calcium hydrogen phosphate, mannitol, maize starch, iron oxide red and magnesium stearate.
Control group
Placebo

Outcomes
Primary outcome [1] 306138 0
Change in proteinuria as measured by urine albumin-creatinine ratio measurement.
Timepoint [1] 306138 0
At baseline, 2 weeks, 6 weeks and 32 weeks (primary time-point) post commencement of intervention for each arm.
Secondary outcome [1] 347707 0
Change in glomerular filtration rate (GFR) as measured by the plasma clearance of technetium-99m-diethylenetriaminepentacetic acid (99mTc-DTPA) method.
Timepoint [1] 347707 0
At baseline and at 32 week visits post commencement of intervention for each arm.
Secondary outcome [2] 347708 0
Change in estimated GFR (eGFR) as measured using serum creatinine based formula.
Timepoint [2] 347708 0
At baseline, 2 weeks, 6 weeks and 32 week (secondary time-point) visits post commencement of intervention for each arm.
Secondary outcome [3] 347709 0
Change in eGFR as measured using serum cystatin C based formula.
Timepoint [3] 347709 0
At baseline and at 32 week visit post commencement of intervention for each arm.
Secondary outcome [4] 347713 0
The difference between serum creatinine based formula and cystatin C based formula in the estimation of GFR.
Timepoint [4] 347713 0
At baseline and at 32 week visit post commencement of intervention for each arm.
Secondary outcome [5] 347715 0
Hospitalisation assessed via medical history taken during clinical assessment.
Timepoint [5] 347715 0
At baseline, 2 week, 6 week and 32 week visits post commencement of intervention for each arm of the study.
Secondary outcome [6] 348271 0
Cardiac function measured using peripheral venous pressure (PVP) via peripheral venous catheter and using a portable pressure monitor with a standard transduction setup.
Timepoint [6] 348271 0
Measured at baseline and at 32 Weeks post commencement of intervention for each arm of the study.

Eligibility
Key inclusion criteria
Participants who:
• Are a minimum 5 years of age AND are a minimum of 12-months post Fontan completion (no maximum age)
• Live in Victoria or New South Wales 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
Minimum age
5 Years
Maximum age
No limit
Gender
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
• eGFR or GFR <30 ml/min/1.73m2
• Bilateral renal artery stenosis
• Uncontrolled hypertension
• Baseline hyperkalaemia (K > 5.5mmol/L)
• Current treatments with potassium sparing diuretics (e.g. spironolactone, amiloride) or NSAIDs (excluding low dose aspirin which is standard of care in many Fontan patients)
• Diagnosis of diabetes mellitus
• Concurrent use of another experimental drug

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using computerised sequence generation and stratified by gender and age.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Based on results from a screening study of 150 patients undertaken by the ANZ Fontan Registry, and after removing outliers and selecting those with elevated urine albumin:creatinine ratio (ACR, greater than 2.5mg/mmol in males or greater than 3.5mg/mmol in females) (primary outcome measure), the mean ACR was 5.7 (SD 3.8). To detect a mean reduction in ACR of 30% with lisinopril therapy, with a two-sided significance level of 0.05 and power of 80%, 40 patients in each group (control and treatment) are estimated to be needed, allowing for a non-compliance adjustment of 10%.
The target sample size is 80 participants recruited from Melbourne and Sydney through The ANZ Fontan Registry.

All analyses will be carried out according to the randomised treatment arm (intention-to-treat), including all eligible randomised patients. Descriptive statistics of baseline characteristics will be reported by randomised arm. For the primary outcome, two one-sided 90% confidence intervals will be used to test for equivalence.

For the secondary outcomes (measured at baseline and 6 months), if follow-up is complete for all participants, the proportion of subjects with each clinical outcome at 6 months (with corresponding exact 95% confidence interval) will be reported for each arm and compared using Fisher’s Exact test; otherwise the Kaplan-Meier method and the log rank test will be used if there is censoring. Summary statistics (mean, standard deviation, median, minimum, maximum) or tabulations of percentages (with exact 95% confidence intervals), will be used to describe clinical parameters at each available visit for each arm. Unless stated otherwise, all statistical tests will be performed two-sided using a significance level of 5% for the secondary outcomes. If confidence intervals are to be calculated, these will be two-sided with a confidence coefficient of 95%.

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)
NSW,VIC
Recruitment hospital [1] 11145 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [2] 11146 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [3] 11147 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 22968 0
3052 - Parkville
Recruitment postcode(s) [2] 22969 0
2050 - Camperdown
Recruitment postcode(s) [3] 22970 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 296182 0
Charities/Societies/Foundations
Name [1] 296182 0
Heart Foundation
Address [1] 296182 0
2/850 Collins Street, Melbourne, VIC, 3008
Country [1] 296182 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Murdoch Children's Research Institute
Address
50 Flemington Road, Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 295092 0
None
Name [1] 295092 0
Address [1] 295092 0
Country [1] 295092 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 297426 0
The Royal Children's Hospital Human Research Ethics Committee (EC00238)
Ethics committee address [1] 297426 0
50 Flemington Road, Parkville VIC 3052
Ethics committee country [1] 297426 0
Australia
Date submitted for ethics approval [1] 297426 0
03/09/2018
Approval date [1] 297426 0
Ethics approval number [1] 297426 0

Summary
Brief summary
Many babies born with a congenital heart condition resulting in only one working heart pumping chamber instead of two undergo a heart operation known as the Fontan procedure. This heart operation enables their heart to function normally however can leave them susceptible to many complications as time goes on, one in particular being kidney damage. There is evidence to suggest (from The ANZ Fontan Registry) that approximately one third of Fontan patients have some degree of kidney damage in the current Australian and New Zealand population. ACEI medications are a class of drugs that have been shown to be effective in improving kidney function and preventing progression of kidney damage, however their effect in Fontan patients is uncertain. This study will evaluate the efficacy of the drug lisinopril, an angiotensin receptor inhibitor (ACEI), on established kidney damage in patients with a Fontan circulation.

The main aim of this project is to find out whether initiation of lisinopril is superior to placebo in reducing the degree of kidney damage and preserving kidney function in children and adults with a Fontan circulation.

We hypothesise that:
1. Lisinopril initiation will significantly reduce the degree of kidney damage and preserve kidney function after a treatment duration of 6 months.

If the hypothesis holds true than it will provide evidence to support the use of ACEI in a subset of Fontan patients with established kidney damage. This would represent a unique group of patients with a clear, testable indication for ACEI therapy after the Fontan procedure.

Future implications of this trial would include establishing a model of care for these patients both in terms of screening and treatment of kidney damage and disease hence reducing the burden of this disease for this population group.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73998 0
Prof Yves d'Udekem
Address 73998 0
The Royal Children's Hospital
Cardiac Surgery Department
50 Flemington Road, Parkville VIC 3052
Country 73998 0
Australia
Phone 73998 0
+61 3 93455203
Fax 73998 0
Email 73998 0
yves.dudekem@rch.org.au
Contact person for public queries
Name 73999 0
Dr Karin du Plessis
Address 73999 0
Murdoch Children's Research Institute
Heart Research Group
50 Flemington Road, Parkville VIC 3052
Country 73999 0
Australia
Phone 73999 0
+61 3 93456161
Fax 73999 0
Email 73999 0
karin.duplessis@mcri.edu.au
Contact person for scientific queries
Name 74000 0
Prof Yves d'Udekem
Address 74000 0
The Royal Children's Hospital
Cardiac Surgery Department
50 Flemington Road, Parkville VIC 3052
Country 74000 0
Australia
Phone 74000 0
+61 3 93455203
Fax 74000 0
Email 74000 0
yves.dudekem@rch.org.au

No data has been provided for results reporting
Summary results
Not applicable