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Clinical Trial Results:
Ballon aortic valvuloplasty performed without heparin to decrease vascular and bleeding complications of the procedure

Summary
EudraCT number	2012-003391-39
Trial protocol	FR
Global end of trial date	25 Oct 2016

Results information
Results version number	v1(current)
This version publication date	13 Aug 2022
First version publication date	13 Aug 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

9026

ISRCTN number

US NCT number

NCT01823393

WHO universal trial number (UTN)

Sponsor organisation name

UH of Montpellier

Sponsor organisation address

Avenue du Doyen Gaston Giraud, Montpellier, France,

Public contact

DRI, Direction de la Recherche et de l'Innovation, 0033 467330924, depotac@chu-montpellier.fr

Scientific contact

DRI, Direction de la Recherche et de l'Innovation, 0033 467330924, depotac@chu-montpellier.fr

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

22 Feb 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

22 Oct 2016

Global end of trial reached?

Yes

Global end of trial date

25 Oct 2016

Was the trial ended prematurely?

Yes

Main objective of the trial

To assess if the non-use of heparin sodium during balloon aortic valvuloplasty reduces serious complications due to the procedure, by decreasing the rate of vascular and hemorrhagic complications without increasing the risk of ischaemic events.

Protection of trial subjects

Constitution of an IDMC that provides patient safety and benefit/risk ratio.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Jan 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 89

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The target population will concern all adult patients justifying balloon aortic valvuloplasty, whatever the indication.

Screening details

Adult patient with tight and symptomatic aortic stenosis of degenerative or congenital origin (bicuspid valve)? with an indication for balloon aortic valvuloplasty

Period 1 title

OVERALL (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

HEPARIN

Arm description

injection of unfractionated heparin (50 IU / kg) Valvuloplasty is performed in a conventional manner, ie with an injection of unfractionated heparin (50 IU / kg) at the start of procedure

Arm type

Experimental

Investigational medicinal product name

HEPARIN

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled injector

Routes of administration

Intravenous use

Dosage and administration details

La dose d'héparine administrée sera de 50UI/kg en IV directe en début de procédure de la valvuloplastie dès la mise en place du désilet. Héparine choay 25 000 UI / 5 ml solution injectable intraveineuse (héparine sodique, flacon de 5 ml), fournisseur laboratoire Sanofi-Aventis France.

PLACEBO NaCl

Arm description

without heparin valvuloplasty is performed without heparin (placebo injection)

Arm type

Placebo

Investigational medicinal product name

NaCl

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion in pre-filled syringe

Routes of administration

Intravenous use

Dosage and administration details

La dose d'héparine administrée sera de 50UI/kg en IV directe en début de procédure de la valvuloplastie dès la mise en place du désilet. Un volume équivalent de Chlorure de Sodium 0.9% (NaCl 0.9%) sera injecté aux patients randomisés dans le groupe placebo. Placebo: Chlorure de Sodium PROAMP 0.9% solution injectable (ampoule de 10 ml), fournisseur laboratoire Aguettant.

Number of subjects in period 1	HEPARIN	PLACEBO NaCl
Started	44	45
Completed	39	43
Not completed	5	2
death	1	-
Lost to follow-up	4	-
Protocol deviation	-	2

Baseline characteristics

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Reporting group title

HEPARIN

Reporting group description

injection of unfractionated heparin (50 IU / kg) Valvuloplasty is performed in a conventional manner, ie with an injection of unfractionated heparin (50 IU / kg) at the start of procedure

Reporting group title

PLACEBO NaCl

Reporting group description

without heparin valvuloplasty is performed without heparin (placebo injection)

Reporting group values	HEPARIN	PLACEBO NaCl	Total
Number of subjects	44	45	89
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	0	2	2
From 65-84 years	19	19	38
85 years and over	25	24	49
Gender categorical
Units: Subjects
Female	21	27	48
Male	23	18	41

Subject analysis set title

Intention to treat

Subject analysis set type

Intention-to-treat

Subject analysis set description

exclusion of patients with consent issues and those who did not have valvuloplasty

Subject analysis sets values	Intention to treat
Number of subjects	82
Age categorical
Units: Subjects
In utero	0
Preterm newborn infants (gestational age < 37 wks)	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	2
From 65-84 years	36
85 years and over	44
Age continuous
Units:
	( )
Gender categorical
Units: Subjects
Female	45
Male	37

End points

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Reporting group title

HEPARIN

Reporting group description

injection of unfractionated heparin (50 IU / kg) Valvuloplasty is performed in a conventional manner, ie with an injection of unfractionated heparin (50 IU / kg) at the start of procedure

Reporting group title

PLACEBO NaCl

Reporting group description

without heparin valvuloplasty is performed without heparin (placebo injection)

Subject analysis set title

Intention to treat

Subject analysis set type

Intention-to-treat

Subject analysis set description

exclusion of patients with consent issues and those who did not have valvuloplasty

Primary: occurrence of a serious complication

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End point title

occurrence of a serious complication

End point description

End point type

Primary

End point timeframe

between inclusion/valvuloplasty and end of study

End point values	HEPARIN	PLACEBO NaCl	Intention to treat
Number of subjects analysed	39	43	82
Units: number	6	1	7

primary endpoint via regression logistic

Statistical analysis description

Analysis of the primary endpoint adjusted for sex, the presence of diabetes, renal failure and arteriopathy of the lower limbs and the closure system + COPD

Comparison groups

HEPARIN v PLACEBO NaCl

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.034

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

11.89

Confidence interval

level

95%

sides

2-sided

lower limit

1.21

upper limit

117.24

Adverse events

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Timeframe for reporting adverse events

immediately upon knowledge of the adverse event

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

ALL GROUPS

Reporting group description

Serious adverse events	ALL GROUPS
Total subjects affected by serious adverse events
subjects affected / exposed	35 / 89 (39.33%)
number of deaths (all causes)	5
number of deaths resulting from adverse events	5
Vascular disorders
Aortic stenosis
subjects affected / exposed	2 / 89 (2.25%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	0 / 1
Haematoma
subjects affected / exposed	4 / 89 (4.49%)
occurrences causally related to treatment / all	1 / 4
deaths causally related to treatment / all	0 / 0
Lymphocele
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Surgical and medical procedures
Aortic valve replacement
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Biliary tract operation
subjects affected / exposed	2 / 89 (2.25%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
fatigue
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Hyperthermia
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Malaise
subjects affected / exposed	2 / 89 (2.25%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Dyspnoea
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Tachypnoea
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Investigations
Angiogram
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Inflammatory marker increased
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Injury, poisoning and procedural complications
Vascular pseudoaneurysm
subjects affected / exposed	3 / 89 (3.37%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Atrioventricular block
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Bradyarrhythmia
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Cardiac failure
subjects affected / exposed	8 / 89 (8.99%)
occurrences causally related to treatment / all	1 / 8
deaths causally related to treatment / all	1 / 3
Nervous system disorders
Aphasia
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Brain stem stroke
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Hemiplegia
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
ischaemic attack
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 89 (5.62%)
occurrences causally related to treatment / all	0 / 5
deaths causally related to treatment / all	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 89 (3.37%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Haematuria
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Renal failure
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Urinary retention
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Urinary tract infection
subjects affected / exposed	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	ALL GROUPS
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 89 (4.49%)
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	4 / 89 (4.49%)
occurrences all number	4

More information

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Were there any global substantial amendments to the protocol? Yes

12 Feb 2013

addition of a co-investigator

10 Jun 2014

extension of the duration of inclusions.

12 Nov 2014

temporary suspension of inclusions following a meeting of the CSI

13 Jan 2015

resumption of inclusions requires the authorizations of the CPP and the ANSM via substantial modification n°4.

12 May 2015

extend the duration of inclusions

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
24 Oct 2014	This decision by the promoter comes following a meeting of the Independent Monitoring Committee (ISC) which took place on September 24, 2014. Indeed, pending additional information from PR LECLERCQ, coordinating investigator, on the seriousness (or not) of the complications that occurred in some patients (primary endpoint) with regard to the protocol in force, the members of the CSI cannot decide whether or not to continue the research.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/35402691

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Clinical trials

Clinical Trial Results:
Ballon aortic valvuloplasty performed without heparin to decrease vascular and bleeding complications of the procedure

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: occurrence of a serious complication

Primary: occurrence of a serious complication

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: Ballon aortic valvuloplasty performed without heparin to decrease vascular and bleeding complications of the procedure

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: occurrence of a serious complication

Primary: occurrence of a serious complication

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Ballon aortic valvuloplasty performed without heparin to decrease vascular and bleeding complications of the procedure