Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000767707
Ethics application status
Approved
Date submitted
20/05/2022
Date registered
30/05/2022
Date last updated
27/09/2023
Date data sharing statement initially provided
30/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The evaluation of Intra-bronchial and Nebulised Bacteriophage Treatment in Children with Cystic Fibrosis and Pseudomonas. (CHIP-CF)
Scientific title
A Single-Arm, Open-Labelled, Safety and Tolerability of Intra-bronchial and Nebulised Bacteriophage Treatment in Children with Cystic Fibrosis and Pseudomonas aeruginosa.
Secondary ID [1] 307181 0
Nil Known
Universal Trial Number (UTN)
U1111-1278-5361
Trial acronym
CHIP-CF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cystic fibrosis 326398 0
pseudomonas infection 326399 0
Condition category
Condition code
Respiratory 323686 323686 0 0
Other respiratory disorders / diseases
Infection 323718 323718 0 0
Other infectious diseases
Human Genetics and Inherited Disorders 323748 323748 0 0
Cystic fibrosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open-label, single-arm study of bacteriophage that has demonstrated obligate lytic activity against each of the study participants’ Pseudomonas aeruginosa.
This selected bacteriophage will be prepared according to established protocols and instilled endo-bronchially (first dose) using an appropriately sized bronchoscope, followed by twice a day of bacteriophage nebulisation for a duration of 7 consecutive days as an inpatient.
The bacteriophages will be obtained through and tested in the Westmead Institute of Medical Research (Iredell Lab).
Sterile transfer of the final lysate into sterile vials will be conducted in the sterile medication preparation room in the pharmacy of the Children’s Hospital at Westmead prior to administration.

Phages that exceed titres of 10*8 PFU/mL when tested using the participant’s own bacterial isolate will be selected. Each selected phage will be amplified using the participants' own bacterial strain to avoid any contamination. Bacterial isolate obtained from participants will be tested using spot plaque testing. Phages selected must not only have lytic activity as demonstrated by the plaque formation but will need to be more than or equal to 10*8 PFU/mL to be considered for therapy.

As for the participants’ bacterial strain, genomics will be performed on the initial bacterial isolate used to perform spot testing on available phages, BAL isolates at the start and at the end of treatment ( if pseudomonas continues to be isolated).
Each participant will be treated with a bespoke bacteriophage. This trial has an element of compassionate/magisterial use as these participants have previously been treated with standard treatment available to treat the infection and continue to isolate Pseudomonas aeruginosa.

The phage solution will undergo regular monitoring throughout the entire study following processes that may reduce the phage titres. Examples of steps that may cause a reduction in phage titres include litre scale cultivation, filtration of phage solution, following exposure to medications (mannitol, dornase alfa and nebulised antibiotics), nebulisation and storage process.

In order to test these bespoke phage solutions, any nebulised medication that the participant is on during the trial will be tested against the selected phage prior to commencing treatment to ensure stability and maintenance of potency. A time-kill curve will be performed before and after in vitro exposure of the medications and phage solution. Additionally, phage titre will be assessed following the addition of these medications to ensure titres remain high (more than or equal to 10*8 PFU/mL ).

Nebuliser used in this study will be a TGA-approved mesh nebuliser. In order to confirm the viability of the phage-nebuliser pairing, all candidate phage will undergo testing to ensure titres remain more than or equal to 10*8 PFU/mL prior to administration. Candidate phage will be nebulised and the nebulised aerosol will be collected and phage titration (spot plaque testing will be performed).

The dose of phage administered will be 10*8 PFU/mL of a single individually tailored phage (bespoke), diluted as appropriate in Pharmacy. Primary packaging of phage solution that is sterile will be in sealed sterile glass flasks. This flask will then be transported to a sterile medication preparation room (in the pharmacy of the Children’s Hospital at Westmead). The solution (1mL of 1x10*8 PFU/mL of phage and added with 3mL of sterile normal saline) will be decanted into non-pyrogenic sterile Type 1 glass vials and sealed. These vials will be stored in a 4°C fridge and labelled. Solution from the vial will be transferred into the nebuliser chamber using a sterile syringe and diluted with sterile saline.

Bronchoscopy will be performed using 1 mL/kg of lavage fluid of normal saline 0.9% will be prepared in total to obtain lavage fluid for microbiology and to aid the bronchoscopy. The remaining 1 mL/kg will be made up of 0.9% normal saline with 8 mL of phage solution (equivalent to 2x10*8 PFU in the total solution or 2 sterile vials of phage solution that contain 1x10*8 PFU/4mL ), therefore 2mL/kg of fluid used during the bronchoscopy. The final solution of 1 mL/kg of phage and saline solution will be instilled in equal aliquots in all five lobes of the lung. This translates to 0.2mL/kg in each lobe.

The subsequent bacteriophage dose will be administered via nebulisation. Phage nebulisation must occur after physiotherapy sessions and/or nebulised mannitol and/or nebulised hypertonic saline and/or nebulised dornase alfa and/or nebulised antibiotics
The nebulised solution will contain 1 x10*8 PFU/4mL and be administered twice daily. The ideal timing of phage dosing should be 12 hours apart (range 10 to 14 hours). This therapy will be continued to complete 7 days of phage treatment ( a total of 14 vials of bacteriophages will be administered)

Therapy for intravenous anti-pseudomonal antibiotics will be done concurrently and will be based on the sensitivity of the most recent Pseudomonas aeruginosa isolate and current dosing and guideline as per the Children’s Hospital Westmead existing antibiotic stewardship and treatment protocols. IV antibiotics and physiotherapy will be continued after completion of phage therapy (to complete 10 to 14 days of inpatient treatment).

Following completion of treatment, regular clinical assessments and repeat lung function will be performed at 3, 6, 9 and 12 months.
Intervention code [1] 323629 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331437 0
Tolerability and safety of intra-bronchial and nebulised bacteriophages against Pseudomonas aeruginosa.

Treatment success will be defined as the absence of the following adverse events:
1. Fever > 38.5°C over 3 consecutive temporally related administration or 3 episodes of temporally related fever above 38.5°C over 48 hours following administration of treatment. Temporally related fever is defined as fever above 38.5°C occurring within 1 hour of the administration of the nebulised bacteriophage.
2. Bronchospasm defined at 15% decline in FEV1% measure pre and post administration of first dose of nebulised bacteriophage despite a reduction of dosing and pre-treatment with inhaled salbutamol.
Timepoint [1] 331437 0
Observation will be performed at 15-minute intervals- this includes saturation, heart rate, temperature, blood pressure. Subsequently, observation at 1 hour and subsequently 4 hourly until next administration of nebulization. This will be continued for each phage administration and will conclude following the last administration of phage solution ( day 7)
Secondary outcome [1] 409874 0
The quantity of colony-forming units (CFU/mL) of Pseudomonas aeruginosa following treatment.
Timepoint [1] 409874 0
within 3 months after commencing treatment.
Sputum samples will be collected as follows:
1. 1 day after bronchoscopy
2. Day 7 and day of discharge from hospital ( between day 10 to 14)
3. 3 months following treatment

Eligibility
Key inclusion criteria
Inclusion criteria
1. Adolescents ( between 12 years and 18 years of age) with cystic fibrosis
2. Positive sputum or bronchoalveolar lavage culture (Pseudomonas aeruginosa) in more than 50% of sputum samples over the past 1 year.
3. Continues to isolate Pseudomonas aeruginosa in sputum despite undergoing Pseudomonas aeruginosa eradication therapy using two anti-pseudomonal antibiotics and/or is currently on suppressive treatment
4. The latest clinical isolates of Pseudomonas aeruginosa taken within 3 months of enrolment are susceptible (demonstrates lytic activity) to available anti-Pseudomonas aeruginosa bacteriophages.
5. Ability to perform spirometry
Minimum age
12 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Children who have received more than 1mg/kg of Prednisolone continuously for more than 7 days before study enrolment.
2. Children that require at least 18 hours/day of non-invasive ventilatory (NIV) support during admission.
3. A current diagnosis of Allergic bronchopulmonary aspergillosis (ABPA).
4. History of hemoptysis in the past 12 months prior to study enrolment.
5. Prior known inability to expectorate sputum.
6. Has undergone solid organ transplantation
7. Positive sputum isolation of Burkholderia cepacia or non-tuberculous mycobacterium within the past 1 year.
8. A positive COVID-19 PCR nasal swab or rapid antigen test with a confirmed COVID-19 infection in the past 6 months prior to enrolment.
9. Within 3 months of having received a booster COVID-19 vaccine or within 6 months of receiving the first dose of vaccine.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
Participant demographic and clinical characteristics and study outcomes will be presented using standard descriptive statistics: mean/median and range for continuous variables and frequency and percentages for categorical variables.
The primary outcome of the proportion of participants who achieve a treatment response will be presented with an exact 95% confidence interval. The secondary outcome of change in sputum bacterial titres will be described by mean/median and range.
For secondary end-point continuous data will be reported using the mean/median range. Additional statistical methods may be employed and will be mentioned separately when used during publication. Data of study participants that drop out of the study will be used up to the last available data point before the drop-out date.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/08/2022
Actual
30/08/2023
Date of last participant enrolment
Anticipated
31/07/2024
Actual
Date of last data collection
Anticipated
2/08/2025
Actual
Sample size
Target
10
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 22413 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 22414 0
Sydney Children's Hospital - Randwick
Recruitment postcode(s) [1] 37578 0
2031 - Randwick
Recruitment postcode(s) [2] 37577 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 311484 0
Hospital
Name [1] 311484 0
Respiratory Department, The Children's Hospital at Westmead
Country [1] 311484 0
Australia
Primary sponsor type
Hospital
Name
Respiratory Department, The Children's Hospital at Westmead
Address
Respiratory Department,
The Children's Hospital at Westmead
Cnr of Hawkesbury and Hainsworth St
2145 Westmead, NSW
Country
Australia
Secondary sponsor category [1] 312884 0
None
Name [1] 312884 0
Address [1] 312884 0
Country [1] 312884 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310947 0
The Sydney Children's Hospital Network Ethics Committee
Ethics committee address [1] 310947 0
The Children's Hospital at Westmead
Cnr of Hawkesbury and Hainsworth St
2145 Westmead, NSW
Ethics committee country [1] 310947 0
Australia
Date submitted for ethics approval [1] 310947 0
15/02/2022
Approval date [1] 310947 0
10/05/2022
Ethics approval number [1] 310947 0
2022/ETH00241

Summary
Brief summary
The objective of this study is to demonstrate that bacteriophage therapy is a safe and well-tolerated adjunct in paediatric patients with cystic fibrosis (CF) with Pseudomonas aeruginosa. Our research questions include;
1. Are bronchoscopically instilled and nebulised bacteriophages safe, tolerable, easily administered and well-tolerated as part of a twice a day treatment regimen for 7 days?
2. Are bacteriophages that are delivered directly into the bronchial tree via bronchoscopy followed by nebulised bacteriophage therapy effective in reducing the colony forming units (CFU/mL) of Pseudomonas aeruginosa within the sputum?
Trial website
Trial related presentations / publications
Public notes
This study will be performed in the Children’s Hospital at Westmead and The Sydney Children’s Hospital, Sydney, Australia ( under the Sydney Children’s Hospital Network). The CF multidisciplinary team currently treats 400 children with Cystic Fibrosis. The study will be conducted initially in an in-patient setting for a duration of 7 inpatient days of bacteriophage treatment in addition to standard CF treatment ( IV antibiotics, physiotherapy to be completed as inpatient for 10 to 14 days). Clinical reviews will be performed at 3, 6, 9 and 12 months following bacteriophage treatment.

This is an open-label, single-arm study of bacteriophage that has demonstrated obligate lytic activity against each of the study participants’ Pseudomonas aeruginosa. This selected bacteriophage will be prepared according to established protocols and instilled endo-bronchially using an appropriately sized bronchoscope.

The subsequent bacteriophage dose will be administered via nebulisation. Phage nebulisation must occur after physiotherapy sessions and/or nebulised mannitol and/or nebulised hypertonic saline and/or nebulised dornase alfa and/or nebulised antibiotics
The nebulised solution will contain 1 x108 PFU/4mL and be administered twice daily.


Contacts
Principal investigator
Name 119458 0
Dr Jagdev Singh
Address 119458 0
Respiratory Department
The Children's Hospital at Westmead
Cnr Hawkesbury and Hainsworth St
Westmead 2145
NSW
Country 119458 0
Australia
Phone 119458 0
+61 298453395
Fax 119458 0
Email 119458 0
jagdev.singh@health.nsw.gov.au
Contact person for public queries
Name 119459 0
Dr Jagdev Singh
Address 119459 0
Respiratory Department
The Children's Hospital at Westmead
Cnr Hawkesbury and Hainsworth St
Westmead 2145
NSW
Country 119459 0
Australia
Phone 119459 0
+61 298453395
Fax 119459 0
Email 119459 0
jagdev.singh@health.nsw.gov.au
Contact person for scientific queries
Name 119460 0
Dr Jagdev Singh
Address 119460 0
Respiratory Department
The Children's Hospital at Westmead
Cnr Hawkesbury and Hainsworth St
Westmead 2145
NSW
Country 119460 0
Australia
Phone 119460 0
+61 298453395
Fax 119460 0
Email 119460 0
jagdev.singh@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The trial result will be disseminated through publication (s) obtained from the data of this clinical trial. Cleaned data, complete protocol may be submitted for review to assist with publication.


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
SourceTitleYear of PublicationDOI
EmbaseSingle-arm, open-labelled, safety and tolerability of intrabronchial and nebulised bacteriophage treatment in children with cystic fibrosis and Pseudomonas aeruginosa.2023https://dx.doi.org/10.1136/bmjresp-2022-001360
N.B. These documents automatically identified may not have been verified by the study sponsor.