CLArithromycin for post-Stroke Pneumonia (CLASP): A prospective, randomised open-label blinded-endpoint (PROBE) phase 3 multicentre trial

Research question

In people with post-stroke pneumonia (PSP), does addition of the immunomodulatory macrolide antibiotic clarithromycin to usual non-macrolide antibiotic treatment lead to improved clinical outcomes and health economic benefits? Background

Pneumonia occurs in around 1 in 10 people admitted to hospital with a stroke. PSP causes harmful systemic and pulmonary inflammation and is associated with worse recovery, higher death rates and increased healthcare costs. Antibiotic treatment of pneumonia after a stroke currently varies between hospitals.

Clarithromycin is a macrolide antibiotic that also reduces harmful inflammation in the lungs. Macrolides are currently only added to antibiotic treatment in around 1 in 10 people with PSP. Our previous research has suggested inclusion of clarithromycin might be beneficial for people with post-stroke pneumonia, but a large-scale randomised trial is now required.

Aims and objectives

Primary objective: Determine whether 5 days of treatment with clarithromycin in addition to usual non-macrolide antibiotic treatment for PSP improves functional outcome at 3 months.

Secondary objectives: Determine whether clarithromycin in addition to usual non-macrolide antibiotic treatment for PSP is safe, reduces mortality at 3 months, reduces urgent readmissions, reduces recurrent stroke or other vascular events, increases home time, improves quality of life, improves stroke-related health status, reduces carer burden, is cost-effective.

Methods

We propose a phase 3 randomised, open-label, blinded endpoint multicentre clinical trial in at least 45 stroke units in the United Kingdom. 1166 people within 14 days of admission to hospital with a stroke, and starting (or within 24h of starting) treatment for pneumonia which does not include clarithromycin or another macrolide, will be included. Participants will be randomly assigned 1:1 to receive either usual non-macrolide antibiotic therapy or usual non-macrolide antibiotic therapy plus clarithromycin 500mg twice daily for 5 days.

The primary outcome is centrally assessed functional outcome using the modified Rankin Scale at 3 months. Secondary outcomes include safety, length of hospital stay, antibiotic use (total number and doses); 3 month mortality, participant quality of life (EQ-5D-5L), stroke-related health status (Stroke Impact Scale), home time (number of days at usual place of residence), Zarit Caregiver Burden Interview, carer quality of life, urgent or unplanned re-admissions, recurrent stroke or other vascular events, health economics.

Timelines for delivery

The grant will last 60 months. In the 18 month internal pilot phase we will recruit 36 sites (80% of total) and 246 participants (21% of the total sample), followed by the main recruitment phase and follow-up to month 54 and close down/final analyses to month 60. Anticipated outcome

The results will directly inform clinical practice and clinical guidelines by providing Level 1 RCT evidence for the use of clarithromycin in PSP. Dissemination

The trial will be publicised to stroke survivors, their carers, the wider public and healthcare professionals. We will update progress on social media and relevant websites in scientific and lay formats. We will present our findings from the trial at meetings for stroke care, and stroke service-user meetings in collaboration with our PPI partners. We will publish in medical journals and produce a final report to the funders.