Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000542695
Ethics application status
Approved
Date submitted
2/05/2023
Date registered
22/05/2023
Date last updated
10/05/2024
Date data sharing statement initially provided
22/05/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of safety and effectiveness of a nebulised phage cocktail in patients with chronic rhinosinusitis (CRS)
Scientific title
Investigator initiated, single-centre double blinded randomised controlled Human Clinical Trial to evaluate and compare the safety, tolerability, and effectiveness of a topical phage-cocktail for the treatment of S. aureus/Methicillin resistant Staphylococcus Aureus (MRSA) exacerbation of therapy refractory CRS vs standard of care.
Secondary ID [1] 308976 0
nil
Universal Trial Number (UTN)
U1111-1288-4224
Trial acronym
The AIRSPACE Trial (AntI-MRSA PhAge Cocktail treatment via Acoustic Enhanced Nebulisers)
Linked study record
ACTRN12616000002482 is a parent study of this study.

Health condition
Health condition(s) or problem(s) studied:
chronic rhinosinusitis 329867 0
Condition category
Condition code
Infection 326774 326774 0 0
Studies of infection and infectious agents
Inflammatory and Immune System 326775 326775 0 0
Other inflammatory or immune system disorders
Respiratory 326900 326900 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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 placebo 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 placebo oral antibiotics are Microcrystalline cellulose capsules.

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.
Intervention code [1] 325990 0
Treatment: Drugs
Intervention code [2] 325991 0
Treatment: Devices
Comparator / control treatment
The control arm (Arm 2) will receive twice daily self-administered sinus nebulisation of placebo bacteriophage cocktail (saline solution) for a period of 28 days and twice daily culture directed antibiotic for 14 days. The size of the control arm will be n=33.

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 placebo will be supplied as 10ml of a clear, colourless sterile saline solution in a plugged syringe.

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 comparator arm will be monitored by asking participants to return empty nebuliser solution vessels and antibiotic 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.
Control group
Active

Outcomes
Primary outcome [1] 334641 0
Change in burden of CRS bacterial infection in sinonasal tract via microbiology assays (assessment of colony forming units)
Timepoint [1] 334641 0
0 days (baseline), 7 days, 14 days, 21 days, 28 days (primary timepoint), 3 months and 12 months after first intervention
Primary outcome [2] 334642 0
Assessment of safety of nebulised bacteriophage via documentation of adverse events. This will be assessed by participant discussion with clinician at time points below and filling in an adverse events diary throughout the study duration.
Given their specific mechanism of action, bacteriophages are not able to infect mammalian cells, and have thus far shown few adverse effects when applied to humans for use as antimicrobial treatments (Chanisvilli, 2012; Brussow, 2005). Possible adverse events include rhinalgia (as per our parent study ACTRN12616000002482, where it was noted as a likely related adverse effect in one out of 9 participants (Ooi, 2019). Given that treatment is localised to the sinuses, any side effects that could arise would most likely be localised to the sinuses. Treatment with bacteriophages has been reported to result in a slight increase in body temperature perhaps due to the bacteria killing effect of bacteriophages but this was not observed in our parent study.
Timepoint [2] 334642 0
Participant discussion with clinician: 0 days (baseline), 7 days, 14 days, 21 days, 28 days (primary timepoint), 3 months and 12 months after first intervention. Adverse Events diary: Filled out daily by participant from 0 days (baseline) to 12 months after first intervention. Adverse events diary collected by research coordinator at 7 days, 14 days, 21 days, 28 days (primary timepoint), 3 months and 12 months after first intervention.
Primary outcome [3] 334643 0
Assessment of CRS symptoms by discharge, inflammation, and polyps/edema (DIP score) by endoscopic examination of the sinonasal tract by the chief investigator.
Timepoint [3] 334643 0
0 days (baseline), 7 days, 14 days, 21 days, 28 days (primary timepoint), 3 months and 12 months after first intervention
Secondary outcome [1] 421497 0
Makeup of the sinus microbiome as assessed by sequencing of DNA extracted from swabs taken of the microbiome by the chief investigator. This is an additional primary outcome.
Timepoint [1] 421497 0
0 days, 28 days (primary timepoint), 3 months and 12 months after first intervention
Secondary outcome [2] 421498 0
Makeup of the sinus proteome as assessed by mass spectrometry of proteins extracted from mucus sponges taken by the chief investigator. This is an additional primary outcome.
Timepoint [2] 421498 0
0 days (baseline), 28 days (primary timepoint), 3 months and 12 months after first intervention
Secondary outcome [3] 421499 0
Assessment of CRS symptoms by participant completion of SNOT 22 (Sino-nasal Outcome Test). This is an additional primary outcome.
Timepoint [3] 421499 0
0 days (baseline), 7 days, 14 days, 21 days, 28 days (primary timepoint), 3 months and 12 months after first intervention
Secondary outcome [4] 421500 0
Retrospective collection of cost data for one year preceding trail enrolment and one year post enrolment to identify cost benefits of phage cocktail vs standard of care treatment. Cost data will be sourced by data-linkage to the Medicare benefits scheme database and the Pharmaceutical Benefits Scheme database. This is an additional primary outcome.
Timepoint [4] 421500 0
One year preceding trial enrolment and one year post enrolment
Secondary outcome [5] 421501 0
Assessment of the presence of anti-phage antibodies in participant serum by analysis of blood samples taken by principal investigator
Timepoint [5] 421501 0
0 days, 28 days, 3 months and 12 months after first intervention
Secondary outcome [6] 421502 0
Measuring markers of inflammation using transcriptomics by evaluating gene expression in nasal epithelial cells using nasal brushings taken from participants by the Chief investigator. This is an exploratory outcome as we will assess the expression of a wide range of genes in an unbiased approach.
Timepoint [6] 421502 0
0 days, 28 days, 3 months and 12 months after first intervention
Secondary outcome [7] 421503 0
Measuring sensitivity of clinical isolates to bacteriophage. Bacterial swabs will be taken from participants by the chief investigator to determine if phage sensitivity is altered after exposure.
Timepoint [7] 421503 0
0 days, 28 days, 3 months and 12 months after first intervention
Secondary outcome [8] 421511 0
Time taken to eradication of bacterial infection in sinonasal tract via microbiology assays (assessment of colony forming units). This is an additional primary outcome.
Timepoint [8] 421511 0
0 days (baseline), 7 days, 14 days, 21 days, 28 days (primary timepoint), 3 months and 12 months after first intervention
Secondary outcome [9] 421946 0
Assessment of CRS symptoms by participant completion of Short Form Health questionnaire (SF12) questionnaire. This is an additional primary outcome.
Timepoint [9] 421946 0
0 days (baseline), 7 days, 14 days, 21 days, 28 days (primary timepoint), 3 months and 12 months after first intervention

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment by randomisation by an external statistician
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary outcome is proportion of patients with eradication of S. aureus/MRSA at day 29. In our phase I trial (ACTRN12616000002482), 2 of 6 patients that received the higher dose phage treatment (the same dose will be given in the proposed study) delivered using nasal rinsing for 2 weeks achieved eradication. Given the expected increase in antimicrobial efficacy when using the nebuliser and high dosage phage treatments for 4 weeks, it is expected that at least 55% of the patients will achieve eradication. Previous research has shown around 20% of rCRS patients achieve eradication of S. aureus infection after multiple courses of culture-directed antibiotics. Using these assumptions, sample size calculations were run based on providing 80% power, with a two-sided alpha of 0.05 for a Fisher’s Exact Test on the primary endpoint. These calculations yielded a sample size of n = 33 patients in each of the control and phage treatment groups.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/01/2024
Actual
19/02/2024
Date of last participant enrolment
Anticipated
15/08/2025
Actual
Date of last data collection
Anticipated
15/08/2026
Actual
Sample size
Target
66
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 24666 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 40285 0
5011 - Woodville South

Funding & Sponsors
Funding source category [1] 313191 0
Government body
Name [1] 313191 0
Department of Health and Aged Care, Medical Research Future Fund
Country [1] 313191 0
Australia
Primary sponsor type
Government body
Name
Central Adelaide Local Health Network
Address
Central Adelaide Local Health Network Inc.
SA Health
Level 3, Roma Mitchell Building
136 North Terrace, Adelaide, SA 5000
Country
Australia
Secondary sponsor category [1] 314902 0
None
Name [1] 314902 0
na
Address [1] 314902 0
na
Country [1] 314902 0
Other collaborator category [1] 282663 0
University
Name [1] 282663 0
University Of Adelaide
Address [1] 282663 0
North Terrace
Adelaide
SA 5000
Country [1] 282663 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312424 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 312424 0
Central Adelaide Local Health Network Inc
SA Health
Level 3, Roma Mitchell Building
136 North Terrace, Adelaide, SA 5000
Ethics committee country [1] 312424 0
Australia
Date submitted for ethics approval [1] 312424 0
01/06/2022
Approval date [1] 312424 0
13/01/2023
Ethics approval number [1] 312424 0

Summary
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 placebo 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
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124614 0
Prof Peter-John Wormald
Address 124614 0
The Queen Elizabeth Hospital and the University of Adelaide
Department of Otolaryngology, Head and Neck Surgery
Tower Block 3C
37 Woodville Road
Woodville South SA 5011
Country 124614 0
Australia
Phone 124614 0
+61882227158
Fax 124614 0
Email 124614 0
pjwormald@gmail.com
Contact person for public queries
Name 124615 0
Prof Sarah Vreugde
Address 124615 0
The Queen Elizabeth Hospital and the University of Adelaide
Department of Otolaryngology, Head and Neck Surgery
Tower Block 3C
37 Woodville Road
Woodville South SA 5011
Country 124615 0
Australia
Phone 124615 0
+61882226928
Fax 124615 0
Email 124615 0
sarah.vreugde@adelaide.edu.au
Contact person for scientific queries
Name 124616 0
Prof Peter-John Wormald
Address 124616 0
The Queen Elizabeth Hospital and the University of Adelaide
Department of Otolaryngology, Head and Neck Surgery
Tower Block 3C
37 Woodville Road
Woodville South SA 5011
Country 124616 0
Australia
Phone 124616 0
+61882227158
Fax 124616 0
Email 124616 0
pjwormald@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We will publish the results of the trial in a suitable scientific journal. This will not include individual participant data, and will include summary tables and statistical analysis only


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.