Effect of Exeporfinium Chloride (XF-73) Gel on Nasal S.Aureus in Patients at Risk of Post-op Staphylococcal Infection

This study looks at the difference between XF-73 and placebo in reducing the carriage of a bacteria S. aureus in the nose before, during and after heart surgery. Only people who normally have S.aureus in their nose will be enrolled onto the study. This will be confirmed by analysis of a nasal swab (a cotton bud placed in the nose) before entering the study. It is expected 125 people will participate in this study. Participation will be confirmed by analysis of a nasal swab (a cotton bud placed in the nose) before entering the study. XF-73 or placebo will be given 5 times, with an equal chance of participants receiving either XF-73 or placebo. During the hospital stay more nasal swabs will be taken to determine the amount of S.aureus present in the participant's nose. Other tests such as blood samples, blood pressure and an examination of the nose and sense of smell will be performed as part of the safety assessment. After the hospital stay participants will be followed up for 30 days or if a device has been inserted into the body as part of the surgery for 90 days to look at the rates of post-operative infection between the placebo and XF-73 groups. The study will run for about 18 months. During this period, an independent data monitoring committee will review the study to make sure that the balance of benefits and risks of participating in the study does not change.

This is a multi-centre, double blind, randomized, placebo-controlled study of multiple applications of a single concentration of XF-73 nasal gel to assess the microbiological effect of XF-73 on commensal S. aureus nasal carriage in patients scheduled for surgical procedures deemed to be at high risk of post-operative S. aureus infection. The study is divided in 4 periods: screening (days -14 to -1) randomization (days -10 to -1), treatment (days -1 and 0) and follow-up (post-last study dose to day 30 or day 90 if an implant is inserted during surgery). Day 0 is the calendar day in which surgery takes place. Only patients who test positive to S. aureus by a centrally-performed rapid diagnostic test will be enrolled in the study. Approximately 125 patients will be randomly allocated in a 1:1 ratio to 0.2% w/w XF-73 nasal gel treatment OR placebo to match XF-73 nasal gel.

The study drug, 0.2% w/w XF-73, or matched placebo will be administered 4 times into each nostril over 24 hours prior to surgery and then a single application immediately upon closure of surgical wound. Additionally, patients may undergo chlorhexidine skin decolonisation ahead of surgery and receive perioperative prophylactic systemic antibiotics in accordance with local practice.

Efficacy will be assessed by S. aureus colonisation from screening to 7 days after surgery as well as by incidence of post-operative staphylococcal infections and use of anti-staphylococcal antibiotics post-surgery. Safety will be assessed by reported adverse events (AEs) from screening up to Day 7 as well as vital signs, physical examination (ENT), clinical laboratory assessments (haematology, clinical chemistry, and urinalysis) and Smell Identification Tests at different time points throughout the study.

The maximum study duration will be 45 or 105 days for each individual (from screening to post-study follow-up visit) depending on whether a foreign implant was inserted during surgery.

An independent data monitoring committee (IDMC) will be set up which will review the safety information from the study, the incidence of post-operative staphylococcal infections and to ensure that the balance of benefits and risks of participating in the study does not change.

Eligibility Criteria:
Individuals who meet all of the following criteria are eligible to participate in the study.

1. Male or female patients between 18 and 75 years of age.
2. Patients who are confirmed nasal S. aureus carriers by polymerase chain reaction (PCR) screen assay, and due to undergo surgical procedure.
3. Patients who are willing to provide written informed consent.
4. Patients who are willing and able (as per Investigator judgment) to complete all protocol specified visits and assessments.
5. Woman of childbearing potential\* with a negative urine pregnancy test (sensitive to 25 IU human chorionic gonadotropin (hCG)).

   * Women of childbearing potential are defined as those women between menarche and menopause who have not undergone permanent sterilisation. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

Individuals who meet any of the following criteria are not eligible to participate in the study.

1. Pregnancy (current) or currently lactating.
2. Uncontrolled acute or chronic illness (as determined by the investigator) in addition to those requiring the planned surgical intervention.
3. History of atopy, allergic reactions or hypersensitivity to the study medication or its components.
4. Current upper respiratory tract infection, cold or influenza with significant nasal symptoms that might impact on the patient's ability to comply with the gel application procedure.
5. History of photosensitivity.
6. Family history of porphyria.
7. Use of intra-nasal topical or systemic antibiotics or anti-infectives within the last 4 weeks before screening. (Patients who screen positive for nasal carriage of S. aureus and receive topical or systemic antibiotics or anti-infectives which are not part of their prophylactic peri-operative SOC between screening and first dose of investigational medicinal product (IMP) will be excluded from the study.) The use of intra-nasal antibiotics or anti-infectives other than the study medication prior to surgery is not allowed.
8. Use of other prescribed or over the counter nasal medication in the last 14 days, or oral decongestants in the last 7 days before first administration of study drug.
9. Participation in a clinical trial within the last 12 weeks before first administration of study drug.
10. Contemporaneous clinically significant abnormalities in vital signs or laboratory analyses reported within 14 days prior to randomization which in the opinion of the Investigator would preclude from the safety assessment of the medication under study.
11. Nasal polyps or significant anatomical or other nasal abnormality that would prevent from appropriate administration of the study treatment or represent an excessive risk for the patient's participation.
12. History of nasal surgery including cauterization.
13. A recent history of frequent epistaxis and/or an episode of epistaxis within 3 months of the planned surgery.
14. Use of in situ nasal jewellery or existence of open nasal piercings.