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Trial registered on ANZCTR


Registration number
ACTRN12621001526864
Ethics application status
Approved
Date submitted
21/09/2021
Date registered
10/11/2021
Date last updated
3/06/2022
Date data sharing statement initially provided
10/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Standardised Treatment And Monitoring Protocol to assess safety and tolerability of phage therapy in adults and children (STAMP study)
Scientific title
Standardised Treatment And Monitoring Protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study)
Secondary ID [1] 305361 0
None
Universal Trial Number (UTN)
U1111-1269-6000
Trial acronym
STAMP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bacterial infections 323697 0
Condition category
Condition code
Infection 321232 321232 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A standardised treatment and monitoring protocol for bacteriophage therapy.

Duration and route of administration of phage will be determined individually for each patient by the principal investigator and will depend on the site of infection, confirmed or suspected pathogens, patient factors (e.g. immune compromise, IV access) and availability of phage products (e.g. formulation, purification). The first two weeks of intravenous phage therapy will be administered in hospital. If phage therapy is planned for longer than two weeks, further treatment can be administered via “Hospital in the Home”-like services. Purely topical, aerosolised or oral/enteral administration of phage can occur in the outpatient setting.

For intravenously administered phage, the dose will be determined by the endotoxin level of the phage product, keeping below accepted human pyrogenic threshold of 5 EU/kg per dose. Within this limit, the aim is to administer at least 10^9 pfu/dose. If a non-intravenous route is selected as the primary route of administration (e.g. nebulised, oral/enteral, topical), the aim is to administer at least 10^10 pfu/dose. Multiple routes of administration may be appropriate for individual patients. The phage will be administered once daily in the morning for the first 2 days and then twice daily for the next 12 days. For critically unwell patients, initial twice daily dosing may be used (i.e. from day 1). For patients planned to receive phage therapy for longer than 14 days, dosing frequency will be determined taking into consideration practical limitations. For patients receiving only non-systemically administered phage products these will be administered once daily throughout the course. Invasive routes of administration (e.g. intra-articular or endobronchial), will be considered additional to the primary route of administration.

Patients receiving 14 days of intravenous or oral/enteral phage therapy (majority of participants), monitoring of blood and other clinical samples will be performed on days 0 (baseline), 2, 4, 8, 11, 15 and 29. Monitoring will include inflammatory and immune responses to phage therapy, microbiological clearance and microbiome changes, and phage kinetics. For patients receiving only non-systemically administered phage products, monitoring of blood and other clinical samples will be performed on days 0 (baseline), 2, 4, 8, 15 and 29 but will not include monitoring of phage kinetics. Phage kinetics will be used to adjust dosing frequency for intravenous and orally administered phage: on once daily treatment if the pre-dose serum phage level by plaque assay is <10^2 pfu/mL, the dose will be increased to twice daily, otherwise continue once daily dosing; on twice daily treatment if the pre-dose serum phage level by plaque assay is >10^2 pfu/mL, the dose will be reduced to once daily, otherwise twice daily dosing will continue. For patients planned to receive longer than 14 days of therapy, ongoing monitoring will be performed on a monthly basis until 1 month after the end of phage therapy.

A self-complete quality-of-life questionnaire (EQ-5D-5L/EQ-5D-Y) will be sent to participants on days 0 (baseline) and 29, and again at 3 and 6 months (from start of phage therapy). For patients receiving longer than 3 months of phage therapy, the survey link will also be sent out at 12 months.
Intervention code [1] 321770 0
Treatment: Other
Comparator / control treatment
No control
Control group
Uncontrolled

Outcomes
Primary outcome [1] 329020 0
Safety and tolerability: assessed through adverse events (AEs), vital signs, and clinical laboratory assessments. Safety will be defined by the absence of serious adverse events (SAEs) attributable to study material (phage) occurring from day 1 (first dose of phage administered) until 2 weeks after completion of therapy. The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all AEs, which will also be assessed for seriousness, relatedness (to phage therapy and the intervention protocol) and severity.
Timepoint [1] 329020 0
2 weeks after completion of therapy
Secondary outcome [1] 401817 0
Additional safety outcomes: Any SAE or any AE attributable to phage therapy occurring from day 1 (first dose of phage administered) until 6 months after completion of phage therapy. The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all AEs, which will also be assessed for seriousness, relatedness (to phage therapy and the intervention protocol) and severity.
Timepoint [1] 401817 0
6 months after completion of phage therapy.
Secondary outcome [2] 401818 0
Feasibility of using a standardised treatment and monitoring protocol will be assessed as the proportion of participants with >80% of Minimum Data Requirements available for analysis. This will be collected from completed electronic case report forms (REDCap database). Minimum Data Requirements will vary according to course of phage therapy administered.
Timepoint [2] 401818 0
2 weeks after completion of phage therapy.
Secondary outcome [3] 401819 0
Exploratory outcome: Clinical response to phage therapy
defined as cure (no evidence of ongoing infection: resolution of all clinical symptoms and signs of infection, radiological and laboratory parameters of infection, and microbiological clearance of target pathogen from site of infection), with or without persisting disability; partial response (improvement in clinical signs and symptoms, radiological or laboratory parameters of disease, but with evidence that infection is not completely resolved; or stabilisation of previously documented decline in function, but without obvious improvements, and evidence that infection is not completely resolved); or no response (evidence of ongoing infection with worsening clinical signs and symptoms, radiological or laboratory parameters of disease). Good clinical response will be defined as all participants assessed as “cured” or with “partial response” at least 2 weeks after completion of phage therapy.
Timepoint [3] 401819 0
2 weeks after completion of phage therapy.
Secondary outcome [4] 401820 0
Exploratory outcome: Quality-of-life indicators will be assessed using EQ-5D-5L/EQ-5D-Y.
Timepoint [4] 401820 0
Baseline (before phage therapy), day 29, and 3, 6 and 12 months after starting phage therapy.
Secondary outcome [5] 401821 0
Exploratory outcome: Microbiological clearance of target pathogen(s) defined as the proportion of participants with sustained microbiological clearance (at least 2 consecutive negative cultures) by the end of the intervention period (including up to day 29).
Timepoint [5] 401821 0
Day 29 (4 weeks after the first dose of phage).
Secondary outcome [6] 401822 0
Exploratory outcome: Microbiological clearance of target pathogen(s) defined as time to clearance (day of first negative culture, measured from first day of phage therapy, among participants with sustained clearance [at least 2 consecutive negative cultures with no further positive cultures during the intervention and follow-up period]).
Timepoint [6] 401822 0
6 months after completion of phage therapy.

Eligibility
Key inclusion criteria
1) Patient for whom at least two suitably qualified clinical specialists have agreed phage therapy should be used
2) A suitable phage(s) product is available that complies with all relevant regulatory requirements for therapeutic administration
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participant, parent or guardian or person responsible has not provided informed consent

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
The primary outcome of the proportion of participants who experience one or more SAEs attributable to study therapy will be presented with a 95% confidence interval (CI). A study of at least 50 participants will enable the proportion who experience an SAE attributable to phage therapy to be estimated with a 95% CI of maximum width ±15%. If the proportion is low the CI will be narrower, and if no participants in 50 experience any such SAE we can be confident that the rate is not higher than 7%.

All trial outcomes will be summarised and presented using standard descriptive statistics: frequencies and percentages for categorical data and mean, standard deviation and range or median, quartiles and range for continuous data and the Kaplan-Meier method for time-to-event variables. Results will be presented overall and by sub-groups. Participants may be sub-grouped according to clinical indication (infectious syndrome), route of administration or phage formulation used, or by patient demographics (e.g. age). Exploratory comparisons for all outcomes between subgroups (e.g. adult vs. paediatric patients; those receiving treatment targeting different groups of organisms [Gram-positive vs. Gram-negative organisms]; or different infectious phenotypes [acute bacteraemia vs. chronic osteoarticular infections]) will use standard statistical methods: t-test, chi-square test, log-rank test and corresponding regression models if applicable.

Safety data will be reported for all participants who received any dose of phage therapy. Clinical response to therapy and microbiological clearance outcomes will be reported for participants who received at least 5 days of phage therapy (cumulative). All other outcomes will be reported for all enrolled participants based on available data with no adjustment for missing data.

Recruitment
Recruitment status
Recruiting
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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 309731 0
Government body
Name [1] 309731 0
National Health and Medical Research Council
Country [1] 309731 0
Australia
Funding source category [2] 309732 0
Government body
Name [2] 309732 0
Australian Government Department of Health
Country [2] 309732 0
Australia
Primary sponsor type
Government body
Name
Western Sydney Local Health District
Address
WSLHD Research and Education Network
Darcy Rd
Westmead
NSW 2145
Country
Australia
Secondary sponsor category [1] 310752 0
None
Name [1] 310752 0
Address [1] 310752 0
Country [1] 310752 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309489 0
Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 309489 0
Corner Hawkesbury Road and Hainsworth Street
Westmead
NSW 2145

Ethics committee country [1] 309489 0
Australia
Date submitted for ethics approval [1] 309489 0
22/10/2021
Approval date [1] 309489 0
22/12/2021
Ethics approval number [1] 309489 0

Summary
Brief summary
A standardised treatment and monitoring protocol for Australian adult and paediatric patients requiring bacteriophage therapy is proposed, with no comparator arm. Patients included are those who have exhausted other therapeutic options for control of their infection and are being treated with phage products according to the special access scheme (SAS) as determined by the Australian Therapeutic Goods Administration (TGA) – so-called “compassionate access”. Patients who are assessed to be suitable for phage therapy will receive this as an adjunct to routine clinical care. The purpose of the study is to standardise therapeutic management and data collection in this setting and to assess overall safety and tolerability of phage therapy, as well as the feasibility of such a standardised national protocol.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114326 0
Prof Jonathan Iredell
Address 114326 0
Centre for Infectious Diseases and Microbiology
Level 4, Westmead Institute for Medical Research
176 Hawkesbury Rd
Westmead NSW 2145
Country 114326 0
Australia
Phone 114326 0
+61286273411
Fax 114326 0
Email 114326 0
jonathan.iredell@sydney.edu.au
Contact person for public queries
Name 114327 0
Dr Ameneh Khatami
Address 114327 0
Clinical School
Level 3, The Children's Hospital at Westmead
Hawkesbury Road
Westmead
NSW 2145
Country 114327 0
Australia
Phone 114327 0
+61298451902
Fax 114327 0
Email 114327 0
ameneh.khatami@gmail.com
Contact person for scientific queries
Name 114328 0
Dr Ameneh Khatami
Address 114328 0
Clinical School
Level 3, The Children's Hospital at Westmead
Hawkesbury Road
Westmead
NSW 2145
Country 114328 0
Australia
Phone 114328 0
+61 2 98451902
Fax 114328 0
Email 114328 0
ameneh.khatami@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Primary endpoints
All secondary and exploratory endpoints
When will data be available (start and end dates)?
Immediately following publication, no end date
Available to whom?
Only researchers who provide a methodologically sound proposal, where the use is not for commercial gain.
Available for what types of analyses?
Only to achieve the aims in the approved proposal
How or where can data be obtained?
Access subject to approvals by Principal Investigators via email (jonathan.iredell@sydney.edu.au or ameneh.khatami@health.nsw.gov.au)


What supporting documents are/will be available?

Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseStandardised treatment and monitoring protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study): protocol for an open-label, single-arm trial.2022https://dx.doi.org/10.1136/bmjopen-2022-065401
EmbasePharmacokinetics/pharmacodynamics of phage therapy: a major hurdle to clinical translation.2023https://dx.doi.org/10.1016/j.cmi.2023.01.021