The Lancet Respiratory Medicine: New therapy could help relieve persistent cough

• 4-10% of adults worldwide have a chronic cough – a cough lasting more than eight weeks.
• Phase 2b clinical trial of drug to treat unexplained chronic cough, a condition that has a significant impact on quality of life, shows promising results.
• Currently, no effective licensed therapies exist for this problem.

A new treatment – called gefapixant – may reduce the frequency of coughing, including in patients who have suffered from a chronic cough for more than 15 years, according to results from a phase 2b clinical trial which lasted 12 weeks and included 253 people, published in

The Lancet Respiratory Medicine

journal.

Between four and 10% of adults worldwide suffer from an unexplained chronic cough. Non-smokers with a chronic cough are likely to have an underlying condition such as asthma, or to have been exposed to dust or fumes in the workplace. However, not all people with conditions such as asthma report a chronic cough. This suggests that it’s caused by a separate process, which may explain why it often does not respond to treatment for underlying conditions.

When a cough is unexplained and unresponsive to treatment, a patient may be described as having cough hypersensitivity syndrome. Until now, there has been no safe, long-term treatment for this. A target for treatment could be reducing hyperexcitability of the neuronal pathways involved in coughing. Gefapixant blocks a receptor involved in the cough reflex.

Previous studies found that gefapixant could reduce the frequency of coughing when given in a high dose (600mg) over two weeks, and that doses as low as 50mg could reduce coughing over a four-day trial when given twice daily. The new trial, which lasted 12 weeks, was randomised, double-blind and placebo-controlled to study how effective three different doses of gefapixant were and their associated side effects.

“Many patients with a chronic cough are driven to seek treatment because of the significant negative impact it can have on their quality of life, but at the moment physicians are unable to help,” says Professor Jacky Smith from the University of Manchester, who led the study. “Ours’ is the first study to report a treatment that is safe and effective over the longer term, and phase 3 trials are already underway with an even larger group of people and over a longer timeframe.” [1]

In the current study, the researchers recruited 253 patients with an unexplained or untreatable cough that had persisted for an average of 14.5 years. The patients were recruited from 44 sites across the UK and US. Most (70%, or 177/253) had never smoked. The average age of patients was 60 and over three-quarters (76%, or 193/253) were women, which resembles the profile of patients who attend cough clinics.

Patients were randomly assigned to receive either a placebo (63 patients) or gefapixant twice daily, every day for 84 days. They were administered one of three doses: 7.5mg (64 patients), 20mg (63 patients) or 50mg (63 patients).

Throughout the study, patients kept a cough severity diary, including reporting how many times they coughed per hour. Cough frequency was also captured objectively, by fitting patients with a sound recording device over four 24-hour periods. During three treatment visits, participants completed a Leicester Cough Questionnaire, and during six visits they rated the severity of their cough on a scale from “no cough” to “worst possible cough”. Clinicians recorded any adverse events that could be associated with treatment.

Before treatment started, patients coughed around 24-29 times per hour. After 12 weeks of treatment, the placebo group coughed 18 times per hour, but this reduced by an additional 37% to 11 coughs per hour in the 50mg group. There were also some reductions in the 7.5mg and 20mg groups, but these were not statistically significant.

The most common side effect seen in the trial was a change in patients’ sense of taste (occurring in three (5%) patients given placebo, six (10%) given 7.5 mg gefapixant, 21 (33%) given 20 mg gefapixant, and 30 (48%) given 50 mg gefapixant). Dysgeusia and other taste-related adverse experiences led to 10 patients in the 50mg group discontinuing with the study, but most patients who continued to receive treatment said they would be happy to continue for at least a year. It is not yet available on prescription, while clinical testing continues.

During the trial, there was one serious adverse event (frostbite) but this was thought to be unrelated to the drug.

The authors note that a limitation of their study is that it recorded a strong placebo effect. For example, the waking frequency of coughs in the placebo group went down from an average of 28 per hour before treatment to 18 per hour after 12 weeks. Previous, smaller studies with gefapixant recorded little change in patients given placebo. The authors suggest that patients’ expectations in this trial may have been affected by positive results from previous studies, as well as by the high likelihood (75%) of being assigned to a treatment group.

Writing in a linked Comment, lead author Dr Richard Irwin (who was not involved in the study) from the University of Massachusetts Medical School, USA, says: “Based on the unadjusted data shown in table 2, there was an incrementally larger decrease in cough frequency with each successively larger dose, with the cough frequency at 50 mg being the lowest, but the absolute frequency of cough is not reported as being statistically different from placebo. Because large placebo effects have been seen in other randomized, placebo-controlled cough treatment studies, the authors took this into account by analyzing cough frequency relative to placebo. When this was done, the improvement with the 50mg dose, but not other doses, did reach statistical significance compared with placebo.”]

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NOTES TO EDITORS

This study was funded by Afferent Pharmaceuticals and supported by the Northern Ireland Clinical Research Network and the UK National Institute of Health Research. It was conducted by researchers from the University of Manchester, Manchester University NHS Foundation Trust, Hull York Medical School, King’s College London, Queen’s University Belfast, the Center for Cough (Florida, USA) and GetStat Solutions, USA. A full declaration of interests for all authors is provided in the paper.

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[1] Quote direct from author and cannot be found in the text of the Article.

Peer-reviewed / Randomised Controlled Trial / People