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    Clinical Trial Results:
    Inhaled furosemide for dyspnoea relief in advanced heart failure

    Summary
    EudraCT number
    		 2015-001468-21
    Trial protocol
    		 GB  
    Global end of trial date
    02 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2022
    First version publication date
    01 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V1.0
    Additional study identifiers
    ISRCTN number
    		 ISRCTN11011373
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Block 60, Churchill Hospital, Oxford, United Kingdom, OX137LE
    Public contact
    Joanna Grogono, Oxford Brookes University, 0044 1865 483257, jgrogono@brookes.ac.uk
    Scientific contact
    Joanna Grogono, Oxford Brookes University, 0044 1865 483257, jgrogono@brookes.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We want to explore whether inhaled furosemide relieves breathlessness in patients with heart failure. To address this question we first need to conduct a pilot study. This pilot study will inform a future clinical trial to test the benefit of adding inhaled furosemide to existing treatment in advanced heart failure patients. The principle research question: - What is the effect on inhaled furosemide on breathlessness in patients with chronic advanced heart failure? Why ask this question? Patients with heart failure often experience breathlessness/dyspnoea which restricts their activities. Furosemide is a prescription drug taken as a tablet or as an injection which makes kidneys produce more urine to remove fluid build-up in heart failure. Over time a third of patients will need more furosemide to get the same response from the kidneys but high level of furosemide can lead to kidney failure. If furosemide is inhaled instead this is known to stop coughing, protect the airwa
    Protection of trial subjects
    All recruited patients were monitored by a qualified cardiologist during the CTIMP intervention phases, and close monitoring of adverse events between interventions occurred via telephone.
    Background therapy
    		 No specific treatments were required - but standard treatments for this patient group (advanced heart failure) were permitted according to usual clinical practice, prescribed and managed by the patient's normal clinicians and not by the study team
    Evidence for comparator
    		 A saline mist comparator was used - there is no direct evidence that saline mist inhalation influences breathlessness in this or any other population, and is safe and well tolerated. On this basis, to avoid any placebo effect, a saline mist inhalation of identical volume (4mls) was used
    Actual start date of recruitment
    17 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    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 to 84 years
    9
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from the heart failure clinic at John Radcliffe Hospital or those under the care of the community heart failure nurses in Oxfordshire

    Pre-assignment
    Screening details
    		 Patients were screened from heart failure clinics /community heart failure services, recruiting patients with at least NHYA class III or greater heart failure. 2 x 2 crossover study with repeated visits in the same patients - the data presented is of aggregate results of the effect of inhaled furosemide versus saline on breathlessness.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject
    Blinding implementation details
    4mls saline matched placebo or 4mls furosemide were used and the treatment unknown to the patient or investigator

    Arms
    Arm title
    		 Saline
    Arm description
    		 4mls saline
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    4mls of saline for inhalation

    Investigational medicinal product name
    Furosemide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Furosemide 40mg in solution for nebulisation at 10mg / ml (i.e. 4mls given, identical to saline placebo in volume).

    Number of subjects in period 1
    		Saline
    Started
    13
    Completed
    13
    Period 2
    Period 2 title
    Post intervention Visit 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    As before, complete blinding of saline or furosemide solutions for inhalation, identical and patients and investigators blinded to treatment

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Saline
    Arm description
    		 Nebulised saline
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    4mls normal saline

    Arm title
    		 Furosemide
    Arm description
    		 Nebulised furosemide
    Arm type
    		 Experimental

    Investigational medicinal product name
    Furosemide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    40mg furosemide in 4mls solution (10mg/ml)

    Number of subjects in period 2
    		Saline Furosemide
    Started
    13
    13
    Completed
    13
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 13 13
    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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 75.8 ± 11.9 -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 9 9
    NYHA class
    Units: Subjects
        III
    		 13 13
        IV
    		 0 0
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    		 169 ± 12 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 80 ± 25 -
    Heart Rate
    Units: beats per minute
        arithmetic mean (standard deviation)
    		 71 ± 13 -
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 127 ± 23 -
    Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 69 ± 14 -
    Subject analysis sets

    Subject analysis set title
    Breathlessness analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients how had undergone the crossover study which involved either nebulised saline or nebulised furosemide given in random order, and the breathlessness responses during an excercise test. Results represent the full analysis of each patient

    Subject analysis sets values
    		 Breathlessness analysis
    Number of subjects
    13
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    75.8 ± 11.9
    Gender categorical
    Units: Subjects
        Female
        Male
    NYHA class
    Units: Subjects
        III
        IV
    Height
    Units: centimetre
        arithmetic mean (standard deviation)
    ±
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    ±
    Heart Rate
    Units: beats per minute
        arithmetic mean (standard deviation)
    ±
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    ±
    Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    ±

    End points

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    End points reporting groups
    Reporting group title
    Saline
    Reporting group description
    		 4mls saline
    Reporting group title
    Saline
    Reporting group description
    		 Nebulised saline

    Reporting group title
    Furosemide
    Reporting group description
    		 Nebulised furosemide

    Subject analysis set title
    Breathlessness analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients how had undergone the crossover study which involved either nebulised saline or nebulised furosemide given in random order, and the breathlessness responses during an excercise test. Results represent the full analysis of each patient

    Primary: VAS for breathlessness

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    End point title
    		 VAS for breathlessness
    End point description
    End point type
    Primary
    End point timeframe
    At end of Excercise test and after nebulisation (crossover trial - summated data)
    End point values
    		 Saline Furosemide
    Number of subjects analysed
    12
    12
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    3.2 ± 15.5
    -0.1 ± 12.7
    Statistical analysis title
    		 VAs comparison
    Comparison groups
    Saline v Furosemide
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.1
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Modified Borg Scale

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    End point title
    		 Modified Borg Scale
    End point description
    End point type
    Primary
    End point timeframe
    At end of Excercise test and after nebulisation (crossover trial - summated data)
    End point values
    		 Saline Furosemide
    Number of subjects analysed
    12
    12
    Units: units
        arithmetic mean (standard deviation)
    0.5 ± 15.6
    2.6 ± 11.3
    Statistical analysis title
    		 MBS analysis
    Comparison groups
    Saline v Furosemide
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.1
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Dyspnoea 12

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    End point title
    		 Dyspnoea 12
    End point description
    End point type
    Primary
    End point timeframe
    At end of Excercise test and after nebulisation (crossover trial - summated data)
    End point values
    		 Saline Furosemide
    Number of subjects analysed
    12
    12
    Units: Units
        arithmetic mean (standard deviation)
    -1.5 ± 10.7
    -6.1 ± 10.9
    Statistical analysis title
    		 D12 analysis
    Comparison groups
    Saline v Furosemide
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events reported during acute administration of inhaled saline or furosemide and during exercise tests only
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Saline
    Reporting group description
    		 -

    Reporting group title
    Furosemide
    Reporting group description
    		 -

    Serious adverse events
    		 Saline Furosemide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Saline Furosemide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 13 (15.38%)
    Nervous system disorders
    Anxiety
    Additional description: Short term anxiety after mist inhalation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
    Additional description: URTI after furosemide inhalation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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