ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12618000204246

Ethics application status

Approved

Date submitted

22/01/2018

Date registered

8/02/2018

Date last updated

3/04/2019

Date data sharing statement initially provided

3/04/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Angiotensin-Converting Enzyme (ACE) inhibitor cessation in the setting of well-functioning Fontan hearts

Scientific title

The effect of ACE inhibitor cessation on cardiac function in the setting of well-functioning Fontan hearts

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1195-4221

Trial acronym

Linked study record

Health condition

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

congenital heart defect

Condition category

Condition code

Surgery

Other surgery

Cardiovascular

Other cardiovascular diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a post-marketing, prospective, multi-centre, parellel design, open-label randomised single-blinded equivalence trial of angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin II receptor blockers (ARB) cessation versus continuation in people greater than 8 years old with a Fontan circulation and preserved ventricular systolic function. The intervention group will cease their ACEI or ARB medication for 12 months. The intervention will not be personalised but adherence will be measured using a medication diary.

Intervention code [1]

Treatment: Drugs

Intervention code [2]

Treatment: Other

Comparator / control treatment

The control group will continue taking their current ACEI/ARB medication in the dose and frequency that they have been prescribed by their treating medical practitioner. Adherence will be measured using a medication diary.

Control group

Active

Outcomes

Primary outcome [1]

VO2 peak within 5% range measured by cardiopulmonary exercise testing.

Timepoint [1]

At baseline and at 12 month visits for each arm

Secondary outcome [1]

Quality of life assessed using PedsQL, CHU-9D, EQ-5D-3L and TBQ

Timepoint [1]

At baseline and at 12 month visits for each arm.

Secondary outcome [2]

Hospitalisation assessed by taking medical history during clinical assessment and patient medical records

Timepoint [2]

At baseline and at 12 month visits for each arm.

Secondary outcome [3]

Heart failure assessed by taking medical history during clinical assessment and patient medical records

Timepoint [3]

At baseline and at 12 month visits for each arm.

Secondary outcome [4]

Arrhythmia assessed using ECG as part of the cardiopulmonary exercise test

Timepoint [4]

At baseline and at 12 month visits for each arm.

Secondary outcome [5]

Death

Timepoint [5]

At baseline and at 12 month visits for each arm.

Secondary outcome [6]

Blood pressure assessed with blood pressure monitor

Timepoint [6]

At baseline and 12 month visits for each arm.

Secondary outcome [7]

NYHA class assessed using Specific Activity Scale

Timepoint [7]

At baseline and at 12 month visits for each arm.

Secondary outcome [8]

Ventricular function assessed using Echocardiogram

Timepoint [8]

At baseline and at 12 month visits for each arm.

Secondary outcome [9]

Degree of AV valve regurgitation assessed using Echocardiogram

Timepoint [9]

At baseline and at 12 month visits for each arm.

Secondary outcome [10]

N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels calculated using a blood test.

Timepoint [10]

At baseline and at 12 month visits for each arm.

Eligibility

Key inclusion criteria

1. Have a Fontan circulation
2. Are taking ACEI or ARB medication for 12 months or more.
3. Can perform a cardiopulmonary exercise test on a cycle ergometer.

Minimum age

8 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Have worse than normal ventricular function.
2. Have greater than mild atrio-ventricular or aortic valve regurgitation.
3. Have systemic hypertension.
4. Have a physical or intellectual impairment preventing exercise testing.
5. Are pregnant or intending to get pregnant during the study period or have been pregnant beyond the first trimester within 12 months prior to study recruitment..

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)

Central randomisation by computer

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

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

The assumptions made for the sample size are as follows:
o Type I error = 5%
o Power = 90%
o Equivalence margin = 5%
o Standard deviation of absolute change in peak VO2 (continuous measure with units %) = 5%
o Adjustment of 12% for drop-out

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 12 months), if follow-up is complete for all participants, the proportion of subjects with each clinical outcome (hospitalisation, heart failure, arrhythmia and death) at 12 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 logrank 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 BP (clinical outcome), NYHA class, ventricular function, degree of AV valve regurgitation, NT-proBNP and quality of life (using PedsQL, CHU-9D, EQ-5D-3L and TBQ) 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

Recruiting

Date of first participant enrolment

Anticipated

1/03/2018

Actual

31/05/2018

Date of last participant enrolment

Anticipated

15/04/2019

Actual

Date of last data collection

Anticipated

15/04/2020

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,VIC

Recruitment hospital [1]

The Royal Childrens Hospital - Parkville

Recruitment hospital [2]

The Children's Hospital at Westmead - Westmead

Recruitment hospital [3]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [4]

Lady Cilento Children's Hospital - South Brisbane

Recruitment postcode(s) [1]

3052 - Parkville

Recruitment postcode(s) [2]

2145 - Westmead

Recruitment postcode(s) [3]

2050 - Camperdown

Recruitment postcode(s) [4]

4101 - South Brisbane

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Heart Kids Australia

Country [1]

Australia

Primary sponsor type

Individual

Name

Prof Yves d'Udekem

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Royal Children's Hospital HREC

Ethics committee address [1]

50 Flemington Rd, Parkville VIC 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

05/05/2017

Approval date [1]

21/11/2017

Ethics approval number [1]

HREC/17/RCHM/79

Summary

Brief summary

This study will look at the impact of angiotensin receptor inhibitors (ACEI) cessation in children and adults with a Fontan circulation and normal heart contraction. Many children born with a single cardiac pumping chamber undergo a Fontan operation. Due to concerns about potential late heart failure, many are prescribed ACEI although they have good heart function, possibly exposing them to unnecessary risk of adverse drug reactions and the burden of lifelong medication. Evidence has shown ACEI are of benefit in a failing 2-ventricle heart, but there is no literature to suggest they are of benefit in the Fontan circulation.

This project aims to demonstrate that cessation of ACEI, or closely related angiotensin receptor blockers (ARB), is safe and non-inferior to ACEI/ARB continuation in children and adults with a Fontan circulation with good cardiac systolic function and without other indications for continuation such as moderate or greater valvar regurgitation and/or hypertension.
We hypothesise that:
1.	Cessation of ACEI or ARB does not result in a significant decline in peak exercise capacity or cardiac function over a 12-month follow-up period.
2.	Cessation of ACEI or ARB results in improved quality of life and reduced medical expenses over 12 months.

If the hypotheses hold true it will dispel a historical concern that will relieve a large number of Fontan patients and their families of an unnecessary burden, improving quality of life and sense of well-being. It will improve the futures and the lives of people affected by childhood heart disease. Lifelong medication carries with it an important psychological burden because of the effects on one’s sense of well-being and “normalness”. This can be especially burdensome for children and their families. Medications also impose a risk of adverse reactions, and may also be costly, for example an adult on a standard dose of ACEI without a Healthcare Card could expect to pay $265 per year. Although, in this current era, we strive for evidence-based medical practice, there is little evidence to guide us in many areas of congenital heart medicine. Some practices, that have been routine for many years, may actually be useless or even cause harm. The implementation of ACEI as a routine for people with the unique single-ventricle Fontan circulation is practiced in many centres, although there is virtually no evidence to support their use. 

Future implications of this trial would include reduced morbidity related to unnecessary medication administration, insight into the disease processes that may or may not contribute to late Fontan failure, a better understanding of the consequences of ACEI use including the social and psychological impact, improved quality of life, and streamlined and improved management strategies for people living with a Fontan heart.

Trial website

Public notes

Contacts

Principal investigator

Name

Prof Yves d'Udekem

Address

Cardiac Surgery Department The Royal Children's Hospital 50 Flemington Road, Parkville VIC 3052

Country

Australia

Phone

+61 3 93455203

Fax

yves.dudekem@rch.org.au

Contact person for public queries

Name

Yves d'Udekem

Address

Cardiac Surgery Department The Royal Children's Hospital 50 Flemington Road, Parkville VIC 3052

Country

Australia

Phone

+61 3 93455203

Fax

yves.dudekem@rch.org.au

Contact person for scientific queries

Name

Yves d'Udekem

Address

Cardiac Surgery Department The Royal Children's Hospital 50 Flemington Road, Parkville VIC 3052

Country

Australia

Phone

+61 3 93455203

Fax

yves.dudekem@rch.org.au

Data sharing statement

Will the study consider sharing individual participant data?

Yes

Will there be any conditions when requesting access to individual participant data?

Persons/groups eligible to request access:
• The results from the test will be available to the treating cardiologist

Conditions for requesting access:
• -

What individual participant data might be shared?

• Only the results from the test will be forwarded to the respective cardiologist to be kept on file. If results fall outside what is considered the 'normal range' for patients with a Fontan circulation these will be fed back to the patients treating cardiologist and the patients.

What types of analyses could be done with individual participant data?

• Data will be available for analysis at the discretion of the coordinating principal investigator.

When can requests for individual participant data be made (start and end dates)?

From:
Start: 24/05/2018 End: 01/04/2020

To:
-

Where can requests to access individual participant data be made, or data be obtained directly?

• The results from the test will first be entered onto a password secure website. They will then be sent to each treating cardiologist.

Are there extra considerations when requesting access to individual participant data?

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

No additional documents have been identified.

Trial Review

Documents added manually

Documents added automatically