Gefapixant and breathing control in long COVID
| ISRCTN | ISRCTN38597726 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN38597726 |
| Sponsor | University of Bristol |
| Funder | Medical Research Council |
- Submission date
- 04/08/2026
- Registration date
- 04/08/2026
- Last edited
- 04/08/2026
- Recruitment status
- Not yet recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
Long COVID is a condition in which people continue to have health problems for many months or years after a COVID-19 infection. It is a big health and economic problem in the UK, still affecting 2 million people in 2024 and costing £8 billion each year. Many people with long COVID experience ongoing breathing difficulties. The cause remains unclear, but growing evidence points to disrupted brain and nervous system control of breathing rather than a lung-specific problem. A key part of this breathing control system is the carotid chemoreflex. This is driven by small organs in the neck called the carotid bodies, which monitor the amount of oxygen and carbon dioxide in the blood, sending signals into the brain adjusting breathing, heart rate and blood pressure. Our recent research shows that the carotid chemoreflex is overly sensitive in people with long COVID without other health problems. Dopamine has been used to study the carotid chemoreflex in disease. However, its systemic off-target effects limit interpretation of results, and the need for intravenous infusion limits its therapeutic potential in chronic conditions. Recently the P2X3 receptor in the carotid body has been identified as driving carotid chemoreflex overactivity in certain diseases, including heart failure.
Gefapixant is an oral tablet licensed for use in the UK and specifically acts on P2X3 receptors. This study aims to determine whether P2X3 blockade via a one-off dose of gefapixant reduces chemoreflex sensitivity in people with long-COVID. We will monitor whether hyperventilation at rest is reduced and breathing efficiency during exercise is improved with acute P2X3 receptor blockade compared to placebo. Our study will determine whether P2X3 receptors are involved in carotid chemoreflex hyperactivity in people with long COVID. Potentially P2X3 receptor blockade could be used as a treatment for patients with long COVID and ongoing breathing difficulties.
Who can participate?
Patients aged 18-75 years with a diagnosis of long COVID and breathlessness that affects their daily lives.
What does the study involve?
Three study visits at the Clinical Research Facility, Bristol. Visit 1 is a screening visit and will involve five questionnaires, a 12-lead ECG, lung function tests, urine dipstick and pregnancy tests, height, weight, office blood pressure measurements, and a blood sample. Participants will also be sent home with a 24-hour blood pressure monitor. Visits 2 and 3 will be identical, except participants will receive a different tablet (gefapixant or placebo) each day in a randomised order. Resting ventilation assessments and hypoxic ventilatory response testing will be completed. A ramped exercise tolerance test will also be performed. Ventilation, blood pressure, oxygen saturation and heart rate will be continuously recorded throughout the visits.
What are the possible benefits and risks of participating?
You will get a heart tracing, full blood pressure screen, and blood tests, which may be of some benefit from a health check-up point of view; however, these tests should not be relied upon for the identification of undiagnosed medical conditions. Taking part in this study will help us understand more about the science underlying long COVID and how the carotid body is involved in it. We want to learn more about the mechanisms of long COVID to help identify a treatment to improve some of the symptoms that people with long COVID experience.
During respiratory (breathing) monitoring, a mask will be fitted that allows us to measure what you are breathing in and out. There are no risks to breathing room air at rest. We will give you a tablet called gefapixant or placebo which we expect will not give any side effects. We will monitor you closely at all times. The main side effect of a single dose is a change in taste, which is reversible and returns to normal following the elimination of gefapixant from the plasma (about 6 hours). A research nurse or doctor will always be present during the study. During the hypoxic ventilatory response testing, breathing nitrogen can cause some short-lived dizziness or light-headedness. The nitrogen can be immediately switched off and clears from the breathing circuit in seconds. Oxygen levels return to normal quickly after the nitrogen is switched off, and additional oxygen can be given if needed. For the bike exercise test, we will ask you to cycle for up to 12 minutes. A research nurse and researcher will be with you at all times, and if you feel unwell, the test can be stopped at any time. The inherent side effects of exhaustive exercise may be experienced.
Where is the study run from?
University of Bristol (UK)
When is the study starting and how long is it expected to run for?
November 2026 to January 2028
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Hazel Blythe, hazel.blythe@bristol.ac.uk, sn18632@bristol.ac.uk
Contact information
Public, Scientific, Principal investigator
University of Bristol, Biomedical Sciences Building
Bristol
BS8 1TD
United Kingdom
| Phone | +44 (0)117 331 1971 |
|---|---|
| emma.hart@bristol.ac.uk |
Scientific
Biomedical Sciences Building, University of Bristol
Bristol
BS8 1TD
United Kingdom
| Phone | +44 (0)117 331 1971 |
|---|---|
| hazel.blythe@bristol.ac.uk |
Study information
| Primary study design | Interventional |
|---|---|
| Allocation | Randomized controlled trial |
| Masking | Blinded (masking used) |
| Control | Placebo |
| Assignment | Crossover |
| Purpose | Basic science |
| Scientific title | Targeting the carotid chemoreflex via purinergic receptors in patients with long COVID and persistent breathing difficulties |
| Study objectives | Aim 1: To determine whether a single dose of a P2X3 receptor antagonist; oral dose of gefapixant: 45 mg) reduces carotid chemoreceptor sensitivity in long COVID patients versus a placebo. Aim 2: To determine whether gefapixant, a single dose of a P2X3 receptor antagonist (gefapixant versus placebo), reduces hyperventilation at rest in patients with long COVID. Aim 3: To determine whether a single dose of a P2X3 receptor antagonist (gefapixant versus placebo) improves breathing efficiency during exercise in patients with long COVID. |
| Ethics approval(s) |
Not yet submitted |
| Health condition(s) or problem(s) studied | People with long-COVID and breathlessness that affects daily life |
| Intervention | A single dose of oral gefapixant (45 mg) tablet will be used as a mechanistic tool to investigate whether P2X3 receptors contribute to carotid chemoreflex hyperactivity in patients with long-COVID We will randomise using Sealed Envelope. The drug and placebo will be received by all patients in a randomised order, so the drug or placebo will be given in visits 2 or 3. |
| Intervention type | Drug |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Gefapixant |
| Primary outcome measure(s) |
|
| Key secondary outcome measure(s) |
1. Resting normoxic tidal volume measured with spirometry, 2-3 hours after taking gefapixant or placebo |
| Completion date | 05/01/2028 |
Eligibility
| Participant type(s) | |
|---|---|
| Age group | Mixed |
| Lower age limit | 18 Years |
| Upper age limit | 75 Years |
| Sex | All |
| Target sample size at registration | 34 |
| Key inclusion criteria | 1. 18-75 years old 2. Self-reported positive PCR or antibody test before vaccination 3. Not hospitalised for any COVID-19 infection 4. Breathlessness affecting their daily lives, measured by Modified Yorkshire COVID-19 Rehabilitation Scale (used in some long-COVID clinics) |
| Key exclusion criteria | 1. Body mass index ≥35 kg/m² 2. Diagnosed with severe asthma or uncontrolled asthma 3. Pregnancy/breastfeeding women 4. Ongoing requirement of oxygen therapy 5. Moderate anaemia (Hb <100 g/dl) 6. Taking antihypertensive, nitrate, steroid or immunosuppressant medication or medication 7. Major illness, e.g., cancer, inflammatory disease (including vasculitis) or receiving palliative care 8. History of organ transplantation or candidate for organ transplantation 9. History of chronic fatigue syndrome prior to COVID-19 infection 10. Diagnosed cardiovascular disease (including current non-benign arrhythmia, chronic heart failure) 11. History of major psychiatric disorder including bipolar disorders, schizophrenia, schizoaffective disorder, major depression 12. Diagnosis of structural lung disease (such as COPD or pulmonary fibrosis) 13. Diagnosed liver or renal disease 14. Congenital or acquired neurological conditions (including dementia), language disorders, repeated or chronic pain conditions (excluding menstrual pain and minor sporadic headaches) 15. Diabetes mellitus 16. Symptoms of febrile illness 2 weeks before experiment 17. Lower respiratory tract symptoms at time of screening visit (visits would be rearranged) 18. Excessive alcohol consumption (>28 units/week) or use of illicit drugs 19. History of tobacco smoking within last 12 months 20. Inability to understand instructions given in English 21. Surgery under general anaesthesia within 3 months 22. History of stroke 23. Heart transplant 24. Coronary revascularisation 25. Haemodialysis or peritoneal dialysis 26. Participating in another study for an investigational medicinal product 27. Any contraindication to gefapixant or its derivatives, or severe drug allergies 28. Estimated glomerular filtration rate (eGFR) <30 ml/min |
| Date of first enrolment | 02/11/2026 |
| Date of final enrolment | 03/01/2028 |
Locations
Countries of recruitment
- United Kingdom
- England
Study participating centre
Bristol
BS2 8DX
England
Results and Publications
| Individual participant data (IPD) Intention to share | No |
|---|
Editorial Notes
04/08/2026: Study's existence confirmed by the Medical Research Council (UK).
