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Trial registered on ANZCTR


Registration number
ACTRN12616000002482
Ethics application status
Approved
Date submitted
8/12/2015
Date registered
6/01/2016
Date last updated
14/12/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1 Investigator Initiated Study to Evaluate the Safety, Tolerability and Preliminary Effectiveness of AB-SA01 in Patients with Chronic Rhinosinusitis Associated with Staphylococcus aureus Infection
Scientific title
A Phase 1 Investigator Initiated Study to Evaluate the Safety, Tolerability and Preliminary Effectiveness of AB-SA01 in Patients with Chronic Rhinosinusitis Associated with Staphylococcus aureus Infection
Secondary ID [1] 286447 0
nil
Universal Trial Number (UTN)
U1111-1174-7807
Trial acronym
nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic rhinosinusitis 294618 0
Condition category
Condition code
Infection 294921 294921 0 0
Other infectious diseases
Inflammatory and Immune System 294922 294922 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Investigator initiated, single-centre, safety study to evaluate the safety and preliminary effectiveness of three dosage regimens of AB-SA01 in patients with chronic rhinosinusitis associated with Staphylococcus aureus Infection. This is a first in human (FIH) study.

A total of 9 participants will be enrolled in the study. Three (3) cohorts of three (3) patients will be serially dosed with AB-SA01 by nasal douche in the following three (3) dosage regimens:
Cohort 1: Twice daily for a period of 7 days with phage at a concentration of 3x10^8 pfu prepared in 240 mL of a NeilMed sinus rinse

Cohort 2: Twice daily for a period of 14 days with phage at a concentration of 3x10^8 pfu prepared in 240 mL of a NeilMed sinus rinse

Cohort 3: Twice daily for a period of 14 days with phage at a concentration of 3x10^9 pfu


The investigational product, AB-SA01, is a sterile solution containing three active lytic S. aureus bacteriophages: Sa87, Sa83 and J-Sa36. The biological material subject of the Application to Import Biological Materials is a therapeutic bacteriophage (phage) mix consisting of three individual (Sa87, Sa83 and J-Sa36) naturally occurring, not genetically modified, Staphylococcus aureus phages.

To ensure adherence to the intervention, patients will be given detailed instructions of how to use the product and follow up calls during the treatment will be made to ensure there is no confusion. Further to this patients will be asked to return all used and unused vials at the completion of the study, at which time they will also be asked questions specifically about compliance.

Intervention code [1] 291524 0
Treatment: Other
Comparator / control treatment
N/A
Control group
Uncontrolled

Outcomes
Primary outcome [1] 294674 0
To assess the safety and tolerability of three dosage regimens of AB-SA01 in patients with Chronic Rhinosinusitis associated with Staphylococcus aureus infection.

Specific assessments to evaluate treatment safety include the following: the frequency and type of adverse events, clinical laboratory testing and vital signs.

This is the first time that AB-SA01 has been used in man, therefore no information is available regarding side effects in humans, so this study may involve risks that are currently unforeseen. No side effects have been seen in animal studies, including one study which involved the treatment of lung infections similar to those that occur in humans. 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.

All treated participants in Cohort 1 will be observed during the dosing period and will undergo telephone follow-up evaluations to Day 14. All treated participants in Cohorts 2 and 3 will be observed during the dosing period and will undergo telephone follow-up evaluations to Day 21. For the first treatment of AB_SA01 patients will be observed for 2hrs with vitals. At the completion of treatment, participants' sinus regions will undergo an endoscopic review to ensure no damage or irritation has occurred during AB_SA01 topical treatment

Patients will also be asked to record there temperatures twice daily in an effort to detect fevers that may be experienced by the patients. An action plan has been devised when a significant fever is detected as described below.

If temperature is determined to be 37.5 - 38.5 degrees Celsius it will be recommended that the participant takes Panadol/ Paracetamol plus or minus Ibuprofen. If at any time temperature is more than 38.5 degrees Celsius, the participant will be asked to contact the clinical site as soon as possible to discuss and arrange a urine test, repeat blood tests and/or an onsite visit for a medical examination. If the fever does not subside after 24 hours, the laboratory results will be reviewed and a decision will be made by the SMC as to whether the participant should continue treatment
Timepoint [1] 294674 0
For the first dose of AB_SA01 patients will be observed for 2hrs with vitals tested pre-dose, immediately post dose, 30 minutes post-dose and 2 hours post-dose.

During the dosing period, patient will be asked to report any adverse events they experience which will be monitored by the study doctors.

Within 14 days pre-dose and 1 day post-final AB_SA01 dose the patient will have an endoscopic examination of there nose.

1 week post final AB_SA01 dose, all patients will be asked to fill in SNOT-22 and VAS questionnaires, and will be followed up over the phone to discuss the patients health and sinusitis condition.
Secondary outcome [1] 313851 0
The preliminary assessment of effectiveness of three dosage regimens of AB-SA01 by determining the presence of S. aureus.

This outcome will be tested by taking a swab at day 1 post-treatment. The swab will be taken from the middle meatus which is the drainage point of all sinuses. The swab will be sent to an external pathology company for isolation and assessment of the bacteria present in the patients sinuses.


Timepoint [1] 313851 0
one day post-treatment completion
Secondary outcome [2] 313853 0
The preliminary assessment of effectiveness of three dosage regimens of AB-SA01 by endoscopic evaluation by the Investigator using the Lund-Kennedy scale.
Timepoint [2] 313853 0
With 14 days pre-dose and one day post-treatment completion
Secondary outcome [3] 317686 0
The preliminary assessment of effectiveness of three dosage regimens of AB-SA01 by patient assessment of symptoms.

To assess this outcome the patients will be asked to fill out two types of symptom questionnaires both pre and post treatment. These include the Sino-nasal outcome test (SNOT-22) and the visual analogue scale (VAS) test. These values are then compared to see if there is any change in patient symptom score following AB_SA01 treatment.
Timepoint [3] 317686 0
Within 14 days pre-dose, one day post-treatment completion and 7 days post-treatment completion.

Eligibility
Key inclusion criteria
1. 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.
2. Participants must have had at least one operation for their chronic rhinosinusitis but should be at least 6 weeks post- operative.
3. Participants must have a positive sinonasal swab that indicates infection of S. aureus in the sinuses that is sensitive to AB-SA01 within 14 days of enrolment.
4. Participants must show evidence of chronic sinusitis by direct endoscopic examination.
5. Participants must have the ability to administer nasal lavage twice daily for the duration of the treatment period.
6. Participants must have impaired quality of life as measured by RSDI.
7. Participants must be male or female aged between 18 and 70 years.
8. Participants must be able to give written informed consent.
9. Participants must have the ability and willingness to attend several visits to the study centre.
10. Participants must have the willingness and ability to comply with the requirements of the protocol as determined by the Investigator.
11. Participants using highly effective, double barrier contraception (both male and female partners) during the study and for 1 month following the dose of AB-SA01.
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.1. Participants with a diagnosis of cystic fibrosis or ciliary dyskinesia.
2. Female participants who are pregnant or breastfeeding.
3. Participants who are immunocompromised.
4. Participants who are actively taking oral steroids or antibiotics.
5. Participants who have used antibiotics within 1 month prior to screening.
6. Participants who have been on active trial therapy within one month of screening.
7. Participants who have a positive sinonasal swab that indicates presence of P. aeruginosa in the sinuses.
8. Any clinically significant laboratory abnormality.
9. 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will be pre-identified prior to clinical appointment and will be sent an invitation to participate including the PICF. During the initial clinical appointment, if the patient fits the inclusion criteria and none of the exclusion criteria, they will be asked to participate. They will be tested for Staphylococcus aureus infection and subsequently the S. aureus is tested for AB-SA01 sensitivity. They will also have a blood test to identify any abnormal blood results that would exlude them from the trial. If the S. aureus is sensitive to AB-SA01 infection and the blood results are normal the patients will receive treatment. Cohort allocation will be determined by study stage, no random allocation will occur.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
In this study all patients will be treated with the same product AB_SA01, however there will be three distinct groups of patients:
Cohort 1: Twice daily AB_SA01 treatment for a period of 7 days with phage at a concentration of 3x10^8 plaque forming units (pfu) prepared in 240 mL of a NeilMed sinus rinse.

Cohort 2: Twice daily AB_SA01 treatment for a period of 14 days with phage at a concentration of 3x10^8 pfu prepared in 240 mL of a NeilMed sinus rinse.

Cohort 3: Twice daily AB_SA01 treatment for a period of 14 days with phage at a concentration of 3x10^9 pfu prepared in 240 mL of a NeilMed sinus rinse.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The sample size chosen for this study was selected without formal statistical power calculation. Approximately 9 participants will be enrolled in the study, 3 in each cohort. These sample sizes are based on what is reasonable in this patient population for preliminary evaluation of safety. It has been determined to be adequate to meet the study objectives.

The following data presentations and summaries will be performed. No formal inferential statistics will be p

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 3621 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 9404 0
5011 - Woodville South

Funding & Sponsors
Funding source category [1] 291015 0
University
Name [1] 291015 0
The University of Adelaide, Department of Surgery
Address [1] 291015 0
Department Otorhinolaryngology
3C Level 3 Main Building, The Queen Elizabeth Hospital, Woodville Road, Woodville 5011, South Australia, Australia
Country [1] 291015 0
Australia
Primary sponsor type
Hospital
Name
The Queen Elizabeth Hospital
Address
The Queen Elizabeth Hospital
28 Woodville rd,
Woodville South, 5011
South Australia, Australia
Country
Australia
Secondary sponsor category [1] 289691 0
None
Name [1] 289691 0
nil
Address [1] 289691 0
nil
Country [1] 289691 0
Other collaborator category [1] 278633 0
Commercial sector/Industry
Name [1] 278633 0
Ampliphi Biosciences Pty. Ltd.
Address [1] 278633 0
AmpliPhi Australia Pty Ltd
Unit 7 27 Dale Street
Brookvale 2100 NSW
Country [1] 278633 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292599 0
HUMAN RESEARCH ETHICS COMMITTEE (TQEH/LMH/MH)
Ethics committee address [1] 292599 0
The Queen Elizabeth Hospital
Ethics: DX465101
Ground Floor, Basil Hetzel Institute
28 Woodville Road
WOODVILLE SOUTH SA 5011
Ethics committee country [1] 292599 0
Australia
Date submitted for ethics approval [1] 292599 0
16/10/2015
Approval date [1] 292599 0
20/11/2015
Ethics approval number [1] 292599 0
HREC/12/TQEHLMH/43

Summary
Brief summary
CRS is a debilitating inflammatory and infection based condition, affecting up to 9% of the Australian population (AIHW, 2010). Currently available therapies to treat this condition include steroids, antibiotics and surgical intervention (Fokkens et al., 2012). Unfortunately there remains a cohort of patients that are resistant to both medical and surgical interventions who experience persistent CRS symptoms, which is termed recalcitrant CRS (rCRS). The presence of bacterial biofilms in the sinonasal tract is one aspect of the condition shown to contribute to this recalcitrance and symptom persistence. Biofilms are 1000-fold more resistant to antibiotics compared to non-biofilm bacterial, making them resistant to the current place antibiotic therapies that are used to treat infections in CRS. There is, therefore, a need to develop novel therapies that are effective against these biofilms if we are to succeed in treating these rCRS patients.

Bacteriophage-based treatment, AB-SA01, could be the answer to the problem of biofilms in rCRS. Bacteriophages or phages, identified almost 100 years ago, are bacterial viruses that specifically target bacterial cells, leading to cell death. 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).
The Primary endpoint of the study is to:
1. To assess the safety and tolerability of three dosage regimens of AB-SA01 in patients with Chronic Rhinosinusitis associated with Staphylococcus aureus infection.

The secondary objectives of the study are:
2. The preliminary assessment of effectiveness of three dosage regimens of AB-SA01 by endoscopic evaluation by the Investigator using the Lund-Kennedy scale.
3. The preliminary assessment of effectiveness of three dosage regimens of AB-SA01 by patient assessment of symptoms.

Trial website
Trial related presentations / publications
We have just commenced data collation, statistical analysis and will be proceeding with manuscript writing soon.
Abstract has been accepted for oral presentation at the ASOHNS ASM in March 2017
Public notes

Contacts
Principal investigator
Name 56158 0
Prof Peter-John Wormald
Address 56158 0
Department of Otorhinolaryngology
The Queen Elizabeth Hospital
28 Woodville Rd,
Woodville South 5011
South Australia
Australia
Country 56158 0
Australia
Phone 56158 0
+61 8 8222 7158
Fax 56158 0
Email 56158 0
peterj.wormald@adelaide.edu.au
Contact person for public queries
Name 56159 0
Prof Peter-John Wormald
Address 56159 0
Department of Otorhinolaryngology
The Queen Elizabeth Hospital
28 Woodville Rd,
Woodville South 5011
South Australia
Australia
Country 56159 0
Australia
Phone 56159 0
+61 8 8222 7158
Fax 56159 0
Email 56159 0
peterj.wormald@adelaide.edu.au
Contact person for scientific queries
Name 56160 0
Dr Mian Ooi
Address 56160 0
Basil Hetzel Institute
University of Adelaide
37 Woodville Rd
Woodville South, 5011
South Australia
Australia
Country 56160 0
Australia
Phone 56160 0
+61 8 8222 7158
Fax 56160 0
Email 56160 0
mianli.ooi@adelaide.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary