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    Clinical Trial Results:
    Randomised Controlled Crossover Trial of Inhaled Furosemide for Dyspnoea Relief in Advanced Heart Failure

    Summary
    EudraCT number
    		 2017-000124-95
    Trial protocol
    		 GB  
    Global end of trial date
    02 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2022
    First version publication date
    29 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V1.0
    Additional study identifiers
    ISRCTN number
    		 ISRCTN14593637
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Office, Block 60, Churchill Hospital, Oxford, United Kingdom, OX37LE
    Public contact
    Hania Piotrowska, Oxford Respiratory Trials Unit, University of Oxford, 0044 01865225552, hania.piotrowska@ouh.nhs.uk
    Scientific contact
    Hania Piotrowska, Oxford Respiratory Trials Unit, University of Oxford, 0044 01865225552, hania.piotrowska@ouh.nhs.uk
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Office, Block 60, Churchill Hospital, Oxford, United Kingdom, OX37LE
    Public contact
    Najib Rahman, University of Oxford,, 0044 1865225205, najib.rahman@ndm.ox.ac.uk
    Scientific contact
    Najib Rahman, Najib Rahman, Oxford Respiratory Trials Unit University of Oxford Churchill Hospital, 0044 1865225205, najib.rahman@ndm.ox.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
    11 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We want to determine whether inhaled furosemide relieves breathlessness in patients with heart failure. This is to test the benefit of adding inhaled furosemide to existing treatment in chronic heart failure. The principle research objective: Determine the effect of inhaled furosemide on breathlessness in patients with chronic heart failure
    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
    01 Nov 2017
    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: 30
    Worldwide total number of subjects
    30
    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)
    0
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients recruited in Oxford, UK. Recruited from December 2017 until November 2020.

    Pre-assignment
    Screening details
    		 Patients screened from out patient cardiology clinics to confirm eligibility criteria, or those from a heart failure community• Participant is willing and able to give informed consent for participation in the trial. • Male or Female, aged 18 years or above. (There is no upper age limit although the investigator will ensure they have the capacity

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Saline and IMP (furosemide) labelled and packaged identically, identical in appearance and allocation and treatment unknown to patient and investigator.

    Arms
    Arm title
    		 Baseline
    Arm description
    		 Baseline characteristics of all patients
    Arm type
    		 Baseline

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    n/a
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    4mls saline given as an inhaled medication over 15 - 20 minutes, nebulised twice per day for 1 week

    Number of subjects in period 1
    		Baseline
    Started
    30
    Completed
    30
    Period 2
    Period 2 title
    Visit 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Saline and IMP (furosemide) labelled and packaged identically, identical in appearance and allocation and treatment unknown to patient and investigator. The study is a two-sequence, two-period, two-treatment crossover trial. The primary treatment effect is the one-week treatment effect of inhaled furosemide versus inhaled saline.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Saline
    Arm description
    		 Inhaled saline for 1 week and then Air Hunger (AH) test
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    n/a
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    4mls saline given as an inhaled medication over 15 - 20 minutes, nebulised twice per day for 1 week

    Arm title
    		 Furosemide
    Arm description
    		 Furosemide 40mg in solution for nebulisation at 10mg / ml (i.e. 4mls given, identical to saline placebo in volume). Given as an inhaled medication over 15 - 20 minutes, nebulised twice per day for 1 week
    Arm type
    		 Experimental

    Investigational medicinal product name
    Furosemide
    Investigational medicinal product code
    n/a
    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). Given as an inhaled medication over 15 - 20 minutes, nebulised twice per day for 1 week

    Number of subjects in period 2
    		Saline Furosemide
    Started
    30
    30
    Completed
    25
    25
    Not completed
    5
    5
         Lost to follow-up
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Baseline characteristics for all recruited patients

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.6 ( 17.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 27 27
    Ethnicity
    Ethnicity
    Units: Subjects
        White
    		 30 30
        Other
    		 0 0
    Smoking status
    Smoking status at recruitment
    Units: Subjects
        Current Smoker
    		 2 2
        Ex-smoker
    		 14 14
        Never Smoker
    		 14 14
    MRC Dyspnoea Score
    Categorised in to class 2, 3, 4 and 5
    Units: Subjects
        Class 2
    		 13 13
        Class 3
    		 7 7
        Class 4
    		 7 7
        Class 5
    		 3 3
    NYHA classification
    New York Heart Association Classification of Heart Failure at baseline
    Units: score
        arithmetic mean (standard deviation)
    		 2.6 ( 0.6 ) -
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 114.8 ( 28.6 ) -
    Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 62.7 ( 15.0 ) -
    Heart rate
    Units: Beats per minute
        arithmetic mean (standard deviation)
    		 66.7 ( 17.5 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 172.4 ( 8.6 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 90.1 ( 24.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Baseline characteristics of all patients
    Reporting group title
    Saline
    Reporting group description
    		 Inhaled saline for 1 week and then Air Hunger (AH) test

    Reporting group title
    Furosemide
    Reporting group description
    		 Furosemide 40mg in solution for nebulisation at 10mg / ml (i.e. 4mls given, identical to saline placebo in volume). Given as an inhaled medication over 15 - 20 minutes, nebulised twice per day for 1 week

    Primary: Chronic Air Hunger Test - 100mm Visual Analogue Score (Primary)

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    End point title
    		 Chronic Air Hunger Test - 100mm Visual Analogue Score (Primary)
    End point description
    On Air Hunger (AH) test days, up to two 10 minute practice AH tests will be conducted to establish familiarity with the breathing circuit and consistency in use of VAS. Participants will undergo the first AH test before inhaling the mist (see Appendix A). This will be followed by a further test of induced AH test after the mist inhalation. The AH test involves one ramp (gradual increasing level of ETCO2 to maximal level of breathlessness tolerated and two 4 min periods of raising inspired CO2; one period (the ‘test’ period) with a level of inspired CO2 that produced 50% AH on the VAS during practice sessions; the other period (the ‘masking’ period) with a level of inspired CO2 that will be varied to ensure that subjects experience similar levels of AH even if sensitivity changes. Participants will rate their AH on a 10 cm VAS scale labelled 'none' (no sensation) at one end, and 'extreme' (an intolerable level) at the other end, every 15 seconds.
    End point type
    Primary
    End point timeframe
    Post 1 week of inhaled saline / furosemide and compared between crossover periods
    End point values
    		 Saline Furosemide
    Number of subjects analysed
    25 [1]
    25 [2]
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    0.9 ( 25.0 )
    0.2 ( 21.5 )
    Notes
    [1] - AH test results not available in 5 patients
    [2] - AH test results not available in 5 patients
    Statistical analysis title
    		 Primary outcome
    Statistical analysis description
    Statistical comparison of dyspnoea relief (100mm visual analogue score) comparing 1 week saline to 1 week furosemide
    Comparison groups
    Furosemide v Saline
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [3]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - No evidence of significant difference

    Secondary: Acute Air Hunger Test - 100mm Visual Analogue Score (Secondary)

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    End point title
    		 Acute Air Hunger Test - 100mm Visual Analogue Score (Secondary)
    End point description
    As before for AH test
    End point type
    Secondary
    End point timeframe
    Acute effects of inhaled saline or furosemide on visits with AH test conducted immediately after inhalation
    End point values
    		 Saline Furosemide
    Number of subjects analysed
    25 [4]
    25 [5]
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    -0.3 ( 23.7 )
    -0.6 ( 22.7 )
    Notes
    [4] - 5 patients did not complete AH test
    [5] - 5 patients did not complete AH test
    Statistical analysis title
    		 Comparison of AH test for acute inhalation
    Comparison groups
    Furosemide v Saline
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78 [6]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [6] - No evidence of significant difference between groups

    Secondary: D12

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    End point title
    		 D12
    End point description
    Dyspnoea 12 measurement of breathlessness during Air Hunger Test
    End point type
    Secondary
    End point timeframe
    During Air Hunger Test
    End point values
    		 Saline Furosemide
    Number of subjects analysed
    25 [7]
    25 [8]
    Units: units
        arithmetic mean (standard deviation)
    -7.8 ( 18.2 )
    -6.2 ( 17.0 )
    Notes
    [7] - 5 patients did not complete AH test
    [8] - 5 patients did not complete AH test
    Statistical analysis title
    		 D12 comparison during AH test
    Comparison groups
    Furosemide v Saline
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Serum BNP post 1 week inhalation

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    End point title
    		 Serum BNP post 1 week inhalation
    End point description
    End point type
    Secondary
    End point timeframe
    Blood measurements post 1 week of inhalation of saline or furosemide
    End point values
    		 Saline Furosemide
    Number of subjects analysed
    20 [9]
    20 [10]
    Units: ng/L
        arithmetic mean (standard deviation)
    13.7 ( 35.4 )
    -6.4 ( 27.0 )
    Notes
    [9] - Blood not collected in 10 patients
    [10] - Blood not collected in 10 patients
    Statistical analysis title
    		 BNP comparison post 1 week inhalation
    Comparison groups
    Furosemide v Saline
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06 [11]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [11] - Borderline evidence of clinically non significant reduction in BNP after inhaled furosemide compared with saline

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events reported during entire study period (3 weeks which encompasses initial inhalation week, 1 week washout and then 2nd inhalation week, total 3 weeks)
    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 / 30 (0.00%)
    0 / 30 (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
    10 / 30 (33.33%)
    15 / 30 (50.00%)
    Cardiac disorders
    Hypotension
    Additional description: Transient hypotension in one patient post inhaled furosemide
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Oedema
    Additional description: Peripheral oedema seen in one patient post inhaled saline
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure
    Additional description: Worsening in known cardiac failure status in 2 patients post inhaled saline
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Confusional state
    Additional description: Confusion transiently in 2 patients post inhaled furosemide.
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Sleep deficit
    Additional description: Sleep disturbance in one patient post inhaled furosemide
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Dysgeusia
    Additional description: Short term altered / metallic test after inhalation of both saline (1) and furosemide (3)
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Appetite disorder
    Additional description: Loss of appetite in 1 patient post inhaled saline and 1 furosemide
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Reflux gastritis
    Additional description: Gastroeosophageal reflux disease in one patient post inhaled furosemide
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Dry mouth
    Additional description: Dry mouth seen in two patients post inhaled furosemide
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Diarrhoea
    Additional description: Short term diarrhoea after furosemide inhalation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hyperventilation
    Additional description: Hyperventilation seen short term after inhaled saline (3) and furosemide (1)
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Dyspnoea
    Additional description: In one patient on inhaled saline
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Rash in one patient post inhaled furosemide
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    urinary freqeuncy
    Additional description: Increased frequency in 1 furosemide patient
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Infections and infestations
    viral illness
    Additional description: Possible viral illness post saline treatment in one patient
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0

    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.
    Aimed for recruitment not achieved.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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