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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2 Study to Assess the Effect of a Repeated Dose of XF-73 Nasal Gel on the Microbiological Burden of Commensal Staphylococcus Aureus Nasal Carriage in Surgical Patients at Risk of Post-operative Staphylococcal Infections

Conditions
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Staphylococcal Infections, Surgical Site Infection

Intervention / Treatment
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* Drug: XF-73
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Individuals who meet all of the following criteria are eligible to participate in the study. Male or female patients between 18 and 75 years of age. Patients who are confirmed nasal S. aureus carriers by polymerase chain reaction (PCR) screen assay, and due to undergo surgical procedure. Patients who are willing to provide written informed consent. Patients who are willing and able (as per Investigator judgment) to complete all protocol specified visits and assessments. 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. Pregnancy (current) or currently lactating. Uncontrolled acute or chronic illness (as determined by the investigator) in addition to those requiring the planned surgical intervention. History of atopy, allergic reactions or hypersensitivity to the study medication or its components. 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. History of photosensitivity. Family history of porphyria. 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. 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. Participation in a clinical trial within the last 12 weeks before first administration of study drug. 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. 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. History of nasal surgery including cauterization. A recent history of frequent epistaxis and/or an episode of epistaxis within 3 months of the planned surgery. Use of in situ nasal jewellery or existence of open nasal piercings.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XF-73<br>0.3 mL applications in each naris of 0.2% w/w XF-73 nasal gel for a cumulative dose of 6.0 mg of XF-73. | Drug: XF-73<br>* XF-73 is a dicationic porphyrin derivative having potent bactericidal properties with a novel mode of action.<br>* Other names: Exeporfinium chloride;|
| Placebo Comparator: Placebo<br>0.3 mL applications in each naris of placebo to match XF-73 nasal gel. | Drug: Placebo<br>* Placebo to match XF-73 nasal gel for colour and viscosity.<br>* Other names: Matched Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in S. Aureus Log CFU/mL From Baseline to Pre-surgery | To demonstrate the efficacy of a 0.2% XF-73 nasal gel in reducing the microbiological burden of nasal S. aureus measured as change in colony forming units (CFU) per millilitre (mL) from baseline to immediately prior to surgery in a patient population at risk of post-operative staphylococcal infection | Baseline (Day-10 to Day-1) to immediately prior to surgery (Day 0) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in S. Aureus Log CFU/mL From Baseline to Immediately Post-surgery | To determine the effect of a 0.2% XF-73 nasal gel on S. aureus nasal burden measured as CFUs/mL in follow-up after last administration. | From baseline (day -10 to Day -1) to immediately post surgery (Day 0) | 
| Change in S. Aureus Log CFU/mL From Baseline to 48 Hours After Surgery | To determine the effect of a 0.2% XF-73 nasal gel on S. aureus nasal burden measured as CFUs/mL in follow-up 48 hours after last administration. | From baseline to follow-up at 48 hours after surgery | 
| Change in S. Aureus Log CFU/mL From Baseline to Immediately After Surgery to 6 Days (± 24hours) After Surgery | To determine the effect of a 0.2% XF-73 nasal gel on S. aureus nasal burden measured as CFUs/mL in follow-up 7 days after last administration. | From baseline to follow-up Day 6 ± 24hours after surgery | 
| Number of Participants With Staphylococcal Post-operative Infections During the 30-day Period After Surgery (90 Days in the Case of Foreign Implant) | To assess the effect of XF-73 on S. aureus nasal carriage in the prevention of post-operative staphylococcal infections (surgical site infection, blood stream infections, and others) during the 30 days post-surgery (90 days in the case of a foreign implant). | From immediately post-surgery to 30 days post surgery (90 days in the case of foreign implant) | 
| Incidence of Treatment-emergent Adverse Events From the First Dose of Study Medication to 6 Days (± 24hours) After Last Dose of Study Medication. | To describe the safety and tolerability of multiple administrations of a 0.2% XF-73 nasal gel in a population of surgical patients at risk of post-operative staphylococcal infections. | Immediately prior to surgery until Day 6 ± 24hours. | 
| Changes in Nasal Examination. | To describe the safety and tolerability of multiple administrations of a 0.2% XF-73 nasal gel in a population of surgical patients at risk of post-operative staphylococcal infections by comparison of changes in ENT specialist nasal examination findings from randomisation to 48hours ± 24hours post surgery. | From Randomisation (Day -10 to Day -1) until 48hours ± 24hours post surgery. | 
| Changes in Brief Smell Identification Test (B-SIT). | To describe the safety and tolerability of multiple administrations of a 0.2% XF-73 nasal gel in a population of surgical patients at risk of post-operative staphylococcal infections by comparison of Brief Smell Identification Test (B-SIT) score, assessment and percentile ranking changes from prior to first dose until Day 6 ±24h post surgery. Patients are asked to identify 12 unique smells; the more smells they identify correctly the higher the score (0-12). Comparison of the individual patient score is then made against their expected percentile ranking dependent on age and sex of the general population to determine if their percentile ranking is normal, abnormal relative to age or deficit relative to younger persons. | From Randomisation (Day -10 to Day -1) until Day 6 ± 24hours post surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-operative, Post-surgical, Infection prevention, Staphylococcus aureus, MSSA, MRSA