Condition category
Circulatory System
Date applied
09/09/2015
Date assigned
09/09/2015
Last edited
14/06/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Heart failure is a serious condition caused by the heart failing to pump blood around the body properly. One of the most common symptoms of heart failure is shortness of breath (dyspnoea). This is because blood is not being pumped out of the heart at a high enough pressure, which leads to blood collecting in the blood vessels. This causes fluid to leak into the lungs (pulmonary oedema), making it more difficult to breathe. Furosemide is a loop diuretic (water pill) which helps the body to make more urine, allowing the body to get rid of excess water and salt. It is commonly used in the treatment of heart failure, as it helps to reduce the build-up of fluid in the lungs, making it easier to breathe. However, patients need to take more and more as time goes on to get the same effect, which can put a lot of strain on the kidneys, eventually leading to kidney failure. If furosemide is inhaled instead of swallowed, it is known to stop coughing, prevent the airways from collapsing, and reduce breathlessness, as it tricks the brain into thinking that the lungs are getting enough air. The aim of this study is to find out whether inhaling furosemide can help to ease the breathlessness of patients with heart failure.

Who can participate?
Medically stable adults with heart failure who have been treated with furosemide for at least three weeks.

What does the study involve?
Each participant attends the Cardiovascular Clinical Research Facility at John Radcliffe Hospital 4 times at weekly intervals. During each visit the participant is randomly allocated to receive four treatments in a random order. The treatments are inhaled as a mist over 15 minutes using one of two breathing patterns.
Treatment 1: furosemide using a slow, deep breathing pattern
Treatment 2: placebo (dummy drug) using a slow, deep breathing pattern
Treatment 3: furosemide using a fast, shallow breathing pattern
Treatment 4: placebo using a fast, shallow breathing pattern
Before and after each treatment, participants undertake a breathlessness test. Between tests, the patients are asked to comment on breathing sensations felt, and choose the best descriptions of breathing and non-breathing sensations from lists of phrases. Before and after each inhalation, the participants also undertake one of two exercise tests, which they are randomly allocated to at the start of the study. They either undertake a 6-minute walk test (6MWT) or a cardiopulmonary exercise test (CPET). They perform the same test on each of their visits. If they are allocated to CPET and are unable to perform the test, then they are offered the 6MWT. During each visit, a cannula is inserted to allow multiple blood samples to be taken at various times before and after the treatment. The participants are also asked to visit the bathroom with a flask to measure their urine volume and are provided with an isotonic sports drink to replace the fluid volume excreted.

What are the possible benefits and risks of participating?
There are no direct benefits of participating in this study. There is a risk that participants will experience side effects from the furosemide used in this study.

Where is the study run from?
John Radcliffe Hospital, Oxford (UK)

When is the study starting and how long is it expected to run for?
September 2015 to June 2016

Who is funding the study?
British Heart Foundation (UK)

Who is the main contact?
Dr Jo Grogono

Trial website

Contact information

Type

Scientific

Primary contact

Dr Jo Grogono

ORCID ID

Contact details

Biological and Medical sciences
Faculty of Health and Life Sciences
Oxford Brookes University
Room S308c
Gipsy Lane campus
Oxford
OX3 0BP
United Kingdom

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

19570

Study information

Scientific title

Inhaled furosemide for dyspnoea relief in advanced heart failure

Acronym

Study hypothesis

The aim of this study is to determine the effect of inhaled furosemide on breathlessness in patients with chronic heart failure and to assess the amount of furosemide that is absorbed into the systemic circulation.

Ethics approval

South Central - Oxford C Research Ethics Committee, 11/09/2015, ref: 15/SC/0480

Study design

Randomised; Interventional; Design type: Treatment

Primary study design

Interventional

Secondary study design

Randomised cross over trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Topic: Cardiovascular disease; Subtopic: Cardiovascular (all Subtopics); Disease: Heart Failure

Intervention

Each patient will attend the Cardiovascular Clinical Research Facility at John Radcliffe Hospital 4 times at weekly intervals. During each visit the patient will be randomly allocated to receive four treatments in a random order.

Treatment 1: Inhalation of 4ml of a 10mg/ml solution furosemide (nebulised as a mist) over 15 minutes using breathing pattern 1 (slow, deep breathing)
Treatment 2: Inhalation of 4ml of 0.9% sodium chloride (saline) (nebulised as a mist) over 15 minutes using breathing pattern 1 (slow, deep breathing)
Treatment 3: Inhalation of 4ml of a 10mg/ml solution furosemide (nebulised as a mist) over 15 minutes using breathing pattern 2 (fast, shallow breathing)
Treatment 4: Inhalation of 4ml of 0.9% sodium chloride (saline) (nebulised as a mist) over 15 minutes using breathing pattern 2 (fast, shallow breathing)

Air Hunger (AH) Breathlessness test: Before and after each inhalation of the furosemide or placebo, patients will undertake the AH form of breathlessness test. Please see section 8.5 (baseline assessments) section ‘vi’ for details of the AH test. The patients 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, at regular intervals.
Between tests, the patients will be asked to comment on breathing sensations felt during trials, and will choose the best descriptions of breathing and non−breathing sensations from lists of phrases.

Exercise tests: Before and after each inhalation, the patients will undertake the exercise test which they will be randomly allocated to at recruitment into trial. They will perform either a 6 minute walk test (6MWT) or cardiopulmonary exercise test (CPET). They will perform the same test on each of their visits and this will not be blinded. This is to assess the feasibility of the 6MWT and CPET in this patient population to guide a future clinical trial. If they were allocated to CPET and are unable to perform the test, then they will be offered the 6MWT.

Blood sampling & urine volume: During each visit, a cannula will be inserted to allow multiple blood samples will be taken at various times before and after inhalation to assay for BNP, NT-pro-BNP, troponin and furosemide. A blood sample will also be taken at Visit 1 to measure serum sodium and potassium and will be corrected prior to inclusion if needed. The patients will also be asked to visit the bathroom with a flask to measure urine volume and will be provided isotonic sports drink to replace the fluid volume excreted.

Intervention type

Drug

Phase

Not Applicable

Drug names

Furosemide

Primary outcome measures

Breathlessness is measured using the visual analogue scale (VAS) before and after the air hunger breathing test (experimentally induced breathlessness.) This breathing test is done both before and after the mist inhalation (either furosemide or saline) on study visits 1, 2, 3 and 4.

Secondary outcome measures

1. Breathlessness is measured Dyspnoea-12 questionnaire before and after the air hunger breathing test (experimentally induced breathlessness) before and after the mist inhalation (either furosemide or saline) on study visits 1, 2, 3 and 4
2. Blood concentration of furosemide is directly measured from the blood before and after the mist inhalation (either furosemide or saline) before and after the mist inhalation (either furosemide or saline) on study visits 1, 2, 3 and 4
3. Urine output is measured after the mist inhalation (either furosemide or saline) as an indirect measure of furosemide absorption on study visits 1, 2, 3 and 4
4. Breathlessness is measured using the visual analogue scale (VAS) and Borg scale for breathlessness before and after the exercise test (cardiopulmonary exercise test, CPET or 6 minute walk test, 6MWT) before and after the mist inhalation (either furosemide or saline) on study visits 1, 2, 3 and 4
5. Exercise tolerance/capacity is measured using the distance walked during the 6MWT or peak work rate, peak VO2 consumption and peak heart rate on CPET before and after the mist inhalation (either furosemide or saline) on study visits 1, 2, 3 and 4
6. Blood concentration of cardiac biomarkers are measured directly before and after the exercise test (cardiopulmonary exercise test, CPET or 6 minute walk test, 6MWT) before and after the mist inhalation (either furosemide or saline) on study visits 1, 2, 3 and 4
7. Breathlessness is measured using the VAS and Dyspnoea-12 before and after the mist inhalation (either furosemide or saline) on study visits 1, 2, 3 and 4

Overall trial start date

25/09/2015

Overall trial end date

30/06/2016

Reason abandoned

Eligibility

Participant inclusion criteria

1. Aged 18 years or above
2. Diagnosed with NYHA stage III or IV heart failure
3. Treated with oral furosemide for at least 3 weeks
4. Ambulatory and clinically stable in the previous 3 months
5. Documented left ventricular ejection fraction (LVEF) of <35%.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 12; UK Sample Size: 12

Participant exclusion criteria

1. Those unable to consent for themselves
2. History of allergic reaction (hypersensitive) to furosemide and/or any of the other ingredients of furosemide or amiloride, sulfonamides or sulphonamide derivatives, such as sulfadiazine or co¬trimoxazole
3. Individuals who are dehydrated or have significant symptomatic postural hypotension
4. Significant renal impairment (eGFR <15) or anuric
5. Significant hepatic impairment/cirrhosis (Child¬Pugh class C)
6. Addison's disease
7. Digitalis intoxication
8. Porphyria
9. Individuals who are immunocompromised
10. Patient with life expectancy <6 months
11. Patients who are inappropriate for saline
12. Co-existent history of significant chronic obstructive pulmonary disease or asthma or interstitial lung disease or nasal polyps
13. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the patients at risk because of participation in the trial, or may influence the result of the trial, or the patient’s ability to participate in the trial
14. Have participated in another research trial involving investigational product in the past 4 weeks
15. Patients who have had an admission to hospital with heart failure within the last 3 months
16. Female patients who are pregnant, lactating or planning pregnancy over the course of trial

Recruitment start date

27/01/2016

Recruitment end date

31/07/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

John Radcliffe Hospital
Headley Way
Oxford
OX3 9DU
United Kingdom

Sponsor information

Organisation

Nuffield Dept. Obstetrics and Gynaecology (UK)

Sponsor details

University of Oxford
Level 3
Women's Centre
John Radcliffe Hospital
Oxford
OX3 9DU
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

British Heart Foundation

Alternative name(s)

BHF

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Available on request

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

14/06/2016: Plain English summary added.