None listed
Conditions
Brief summary
Chronic rhinosinusitis (CRS) is a debilitating and costly disease. Consistent inflammation and infection of the sinuses causes headaches, facial pain, blockage of the nose and discharge from the nose. The cause of this condition is not fully understood, and is difficult to treat, with surgery often being recommended. But even after surgery, symptoms return, and repeat surgeries may be needed. CRS patients are often prescribed oral antibiotics for recalcitrant infections. Antibiotics may reduce the bacterial load but are ineffective at eradicating the infection completely. This, and the worldwide issue of antibiotic resistance, are impetus to develop alternative treatments, including a novel bacteriophage cocktail that has been shown to be safe and effective when incorporated into a sinonasal rinse in a pilot clinical trial (ACTRN12616000002482). However nasal irrigations have limitations their ability to penetrate the sinuses, and it is also estimated that a large proportion of the active product is lost without mucosal contact. Therefore, we developed a unique specifically designed device that can effectively deliver phages into the sinonasal cavities. We aim to conduct a double-blinded randomised controlled trial, comparing use of a novel bacteriophage cocktail administered using this specially designed nebuliser to standard-of-care oral antibiotics, in their ability to eradicate therapy refractory S. aureus in CRS patients. 66 participants would be assigned to one of two arms. Arm 1 would receive phage cocktail through the nebuliser twice daily for 28 days, and would receive culture directed oral antibiotics twice daily for 14 days. Arm 2 would receive placebo cocktail through the nebuliser twice daily for 28 days, and culture directed oral antibiotics twice daily for 14 days. Participants would visit their doctor at day 1, 7, 14, 21, 28, and at 3- and 12-months post intervention. A health economic analysis of the period before and after the treatment would also take place to compare the cost of phage treatment to standard-of-care
Interventions
Patients with symptomatic refractory chronic rhinosinusitis who have had previous sinus surgery and have evidence of chronic rhinosinusitis on endoscopic examination will be recruited into this trial.
Patients will be blindly, randomly selected into either the control or intervention arm. The intervention arm will be n=33 participants. Treatments and medical devices will be dispensed and explained to the participants after informed consent has been gained at the outpatient clinic at The Queen E
Patients with symptomatic refractory chronic rhinosinusitis who have had previous sinus surgery and have evidence of chronic rhinosinusitis on endoscopic examination will be recruited into this trial. Patients will be blindly, randomly selected into either the control or intervention arm. The intervention arm will be n=33 participants. Treatments and medical devices will be dispensed and explained to the participants after informed consent has been gained at the outpatient clinic at The Queen Elizabeth Hospital (TQEH) or the private rooms of the Chief investigator. These tasks will be performed by the laboratory research coordinator. The treatment arm (Arm 1) will receive twice daily sinus nebulisation of clinical grade S. aureus bacteriophage cocktail for a period of 28 days and twice daily culture directed antibiotic for 14 days. The nebuliser device used will be the P&S T360 Tekceleo patented MICRONICE™ device with add-on acoustic components. This device has a 12-micrometer vibrating mesh to impact droplet size and delivery to the nose and sinuses. A small pump circulates the liquid drug in a closed circuit where the 12-micrometer vibrating mesh nebulises the circulating liquid. A nozzle directs the aerosol droplets into one side of the nose at a time. The Bacteriophage cocktail investigational product (IP) is a sterile solution containing strictly lytic S. aureus bacteriophages that have been fully characterised at the Adelaide Phage Therapy Centre at The Queen Elizabeth Hospital and are called APTC-SA-2, APTC-SA-4, APTC-SA-13, and APTC-SA-12. They are made in a contract manufacturing facility specialising in phage drug substance production to a GMP-like, United States Pharmacopeia (USP) standard (JAFRAL d.o.o., Ljubljana, Slovenia, E.U.). The final IP will be supplied as 10ml of a clear, colourless solution in a plugged syringe comprising a cocktail of the four phage Drug Substance (DS) at a 1:1:1:1 ratio. It will be administered as a nebulized formulation at a final dose of 1x10^10 Plaque Forming Units (PFU) (4 x 0.25x10^10 PFU). The culture directed antibiotic for participants with S. aureus infection will be amoxicillin/ clavulanic acid 875/125, 1 tablet twice daily for 10 days. If the participant has a penicillin allergy, they will be given doxycycline 100mg daily for 10 days. The culture directed antibiotic for participants with methicillin resistant staphylococcus aureus (MRSA) infection will be advised by the principal investigator upon examination of their Microbiology, culture and sensitivity results. These are standard of care (SOC) for CRS patients. Adherence to the intervention will be monitored by asking participants to return empty nebuliser solution vessels and placebo capsule containers to the investigators. Participants will also bring the nebulisers with them to each clinic appointment to be cleaned and to ensure that they are working correctly. This will be done by passing a constant volume of water through them and ensuring this volume has passed through in the appropriate time frame.
Sponsors
Central Adelaide Local Health Network
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
• Participants must have had at least two of the following symptoms of chronic rhinosinusitis (nasal discharge, postnasal drip, nasal obstruction, facial pain and pressure or lack of sense of smell) that has been previously persistent for greater than 3 months. • Participants must have had at least one operation for their chronic rhinosinusitis but should be at least 3 months post-operative. • Participants must present with signs and symptoms of acute infectious exacerbation of S. aureus or MRSA CRS with positive microbial cultures, • Participants must be sensitive to clinical grade S. aureus bacteriophage and to antibiotics. A nasal swab will be collected from the patient prior to recruitment and sensitivity to the bacteriophage cocktail and to antibiotics will be determined via testing of the patient’s clinical isolate. • Participants must show evidence of chronic sinusitis by direct endoscopic examination. • Participants must have the ability to administer twice daily sinus nebulisations for the duration of the treatment period. • Participants (male or female) must be over 18 years. No upper age limit, at discretion of treating doctor. • Participants must be able to give written informed consent. • Participants must have the ability and willingness to attend several visits to the study centre. • Participants must have the willingness and ability to comply with the requirements of the protocol as determined by the Investigator. • Females of childbearing potential must have a negative pregnancy test prior to enrolment and will be advised through the Informed Consent process to avoid becoming pregnant over the duration of the study, and must assert that they will employ an effective form of birth control for the duration of the study.
Exclusion criteria
• Participants must not have a sinonasal swab that is positive for Pseudomonas aeruginosa • Participants must not have Graft-versus-host disease (GVHD) or be on immunosuppressive therapy • Participants who are unlikely to comply with the study protocol or, in the opinion of the investigator, would not be a suitable candidate for participation in the study. • Females must not be breastfeeding.
Outcome results
None listed