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Trial registered on ANZCTR


Registration number
ACTRN12619001327178
Ethics application status
Approved
Date submitted
19/08/2019
Date registered
27/09/2019
Date last updated
23/06/2024
Date data sharing statement initially provided
27/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Bacillus Calmette Guerin (BCG) vaccination/revaccination for prevention of Mycobacterium tuberculosis infection in healthcare students entering clinical training: A randomised placebo controlled proof of principle trial (PoP BCG trial)
Scientific title
BCG vaccination/revaccination for prevention of Mycobacterium tuberculosis infection in healthcare students entering clinical training: A randomised placebo controlled proof of principle trial (PoP BCG trial)
Secondary ID [1] 299069 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PoP BCG trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infection 314100 0
tuberculosis 314102 0
Condition category
Condition code
Infection 312477 312477 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
BCG vaccine: a freeze-dried vaccine, which contains live attenuated of Mycobacterium bovis. We will use BCG vaccine manufactured by PT Biofarma Indonesia derived from the Pasteur 1173P strain. Each ampoule (20 doses) of vaccine contains: Live attenuated Bacillus Calmette-Guerin 1.5 mg semi-dried basil (1.5-6 million culturable particles), monosodium glutamate 7.5 mg. Each 1 mL of diluent consists of: Sodium Chloride 9 mg, Water for injection adds 1 mL.

Dosing and administration
BCG vaccination: 1 adult dose (0.1 mL) of vaccine (which reconstituted by 4 mL diluent) is administered intradermal with a 22-gauge needle.
Intervention code [1] 315338 0
Prevention
Comparator / control treatment
Placebo: normal saline will be provided and equivalent to the BCG injection (0.1ml). It will be administered on day 0 by intradermal injection with a 22-gauge needle.
Control group
Placebo

Outcomes
Primary outcome [1] 321118 0
Acceptability of the intervention: the proportion of participants who consent and accepted to be given the intervention (BCG vaccine or placebo) over the total number of eligible participants in the study.
Timepoint [1] 321118 0
Baseline - Randomisation day
Primary outcome [2] 321119 0
Adverse events: the proportion of participants who experience any adverse events. Adverse event outcomes will include solicited adverse events (AEs) reported through 7 days after vaccination and unsolicited adverse events reported through one month after vaccination, injection site assessments performed at day 0 post injection, 7 days, and after one month, other AEs reported until end of study.

Adverse events will be reported on the adverse event case report form (CRF) using a recognised medical term or diagnosis that accurately reflect the event. Adverse event evaluations will be reviewed by the PI or by a designated medically qualifier practitioner. Adverse event CRF pages are to be completed by designated study team. The onset and resolution dates of the event and action taken in response to the event will be documented. All adverse events will be followed until resolution is demonstrated. The resolution date will be recorded on the CRF as the last date on which the subject experienced the adverse event. If an adverse event resolution date is uncertain the PI or designee should estimate the completion date based on medical judgment and interview of the subject.
Timepoint [2] 321119 0
Adverse event will be assessed for each participant until 12 months post-vaccination.
Primary outcome [3] 321120 0
Completeness of the study: the proportion of participants who complete follow-up, including all tests.
Timepoint [3] 321120 0
12 months
Secondary outcome [1] 374046 0
IGRA test conversion: the key endpoint will be cumulative IGRA test conversion (using QuantiFERON-TB Gold Plus or QFT-Plus), defined as IGRA test conversion at any time point during the study (at 3, 6, 9 or 12 months). IGRA test conversion will be defined as a change from a negative to a positive test plus a minimum 30% increase in TB1 minus Nil or TB2 minus Nil over the baseline value [Veerapathran et al.]. Secondarily, we will assess persistent IGRA conversion defined as at least two consecutive IGRA tests over follow-up. Exploratory analyses will consider various combinations of IGRA test results across the four follow-up points. A sensitivity analysis will re-analyse the data based on a definition of IGRA test conversion that simply requires a change from a negative to a positive test.
Timepoint [1] 374046 0
3, 6, 9 and 12 months
Secondary outcome [2] 374047 0
Induction of trained immunity (only assessed in 100 of 150 total participants):
The primary readout for immune cell function will be cytokine production of peripheral blood mononuclear cell (PBMCs) in response to BCG, M. tuberculosis and a range of unrelated microbial stimuli; the increase of ex-vivo monocyte-derived and lymphocyte-derived pro- inflammatory cytokine production capacity following BCG vaccination/revaccination will be used as an established marker of trained immunity.

Timepoint [2] 374047 0
at baseline, 1 month, and 3 months
Secondary outcome [3] 374048 0
Changes in DNA methylation of monocytes associated with BCG vaccination/revaccination: DNA methylation of monocytes (using whole blood) will be measured by reduced-representation bisulphite (RRBS) at baseline and 3 months. This will be an exploratory analysis.
Timepoint [3] 374048 0
baseline and 3 months
Secondary outcome [4] 374977 0
Epigenetic changes associated with BCG vaccination/revaccination and immunophenotype of innate cells. Genetic variation will be assessed by a genome-wide SNP array from Illumina. This would be an exploratory outcome.
Timepoint [4] 374977 0
at baseline, 1 month, and 3 months

Eligibility
Key inclusion criteria
1. Medical or nursing students who start their clinical training at Hasan
Sadikin Hospital
2. Tested IGRA negative at screening
3. Tested HIV negative at screening
4. Completed the written informed consent
Minimum age
18 Years
Maximum age
30 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Retraining nursing students (retraining to transform their nursing
qualification into a degree)
2. A positive prior tuberculin skin test (TST) and/or IGRA
3. A history of treatment for TB disease or latent TB infection
4. A history or evidence of TB disease
5. For female students: currently pregnant or lactating/nursing; or positive
urine pregnancy test during screening
6. History of autoimmune disease or immunosuppression or used
immunosuppressive medication

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Trial- group assignment will be concealed by an interactive web-response system. The assignment will be based in block randomisation in a 1:1 ratio to BCG vaccination/revaccination and placebo. Administration of the vaccine and placebo will be blinded (patient and administrator).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
General approach:
The analyses will be descriptive in nature and provide initial estimates of key parameters needed to inform the design of a future randomised clinical trial (RCT). The quantitative measures will be used to address the research questions relating to the acceptability and the feasibility of conducting a definitive trial in the future. Data will be analysed at the end of the study when all data collection, entry, and validation are completed.

Analysis of the primary endpoints:
Acceptability, adverse events, and completion: The proportion of participants and 95% confidence intervals will be presented for each endpoint.

Analysis of the secondary endpoints:
IGRA test conversion: To estimate the cumulative IGRA test conversion, the number of participants who have IGRA test conversion at any time point during the study (at 3, 6, 9 or 12 months) will be used as the numerator and number total of participants included in the study will be used as the denominator. The cumulative IGRA test conversion will be presented with 95% confidence intervals. To estimate persistent IGRA conversion, the number of participants who have at least two consecutive IGRA tests over follow-up, or three consecutive IGRA tests over follow-up will be used as the numerator and the number total of participants included in the study will be used as the denominator.

Induction of trained immunity: We will compare participants of the intervention and control arms in terms of immune cell distribution and function at baseline, 1 month and 3 months after BCG vaccination/placebo.
Trained immunity: We will measure proportional difference in the distribution, function (cytokine production) and epigenetic and gene-transcriptional signature of circulating immune cells before and after BCG vaccination as established marker of trained immunity.

Flow cytometry
Changes in the absolute cell count and phenotype of different innate immune cell populations from baseline to 1 month and baseline to 3 months will be compared between BCG and placebo recipients.

DNA methylation of monocytes
In this exploratory analysis methylation sites will be mapped to the GRCh38 build of the human genome using the Bismark aligner. Differentially methylated sites between baseline and 3 month time points will be compared for BCG re-vaccinated and placebo recipients using the differential Methylation Analysis Package (DMAP). Proximal genes will be identified using the DMAP identgeneloc program and gene ontology will be explored using the GeneCards database (www.genecards.org).

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/08/2023
Actual
2/05/2023
Date of last participant enrolment
Anticipated
30/09/2023
Actual
30/09/2023
Date of last data collection
Anticipated
31/10/2024
Actual
Sample size
Target
150
Accrual to date
Final
150
Recruitment outside Australia
Country [1] 21776 0
Indonesia
State/province [1] 21776 0
Bandung, West Java

Funding & Sponsors
Funding source category [1] 303603 0
University
Name [1] 303603 0
University of Otago
Country [1] 303603 0
New Zealand
Funding source category [2] 303604 0
Government body
Name [2] 303604 0
Health Research Council
Country [2] 303604 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
362 Leith St, North Dunedin, Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 303697 0
None
Name [1] 303697 0
Address [1] 303697 0
Country [1] 303697 0
Other collaborator category [1] 280914 0
University
Name [1] 280914 0
Universitas Padjadjaran
Address [1] 280914 0
Jl Prof Eykman No. 38 Bandung 40161
Country [1] 280914 0
Indonesia
Other collaborator category [2] 280915 0
University
Name [2] 280915 0
Radboud University Medical Center
Address [2] 280915 0
Geert Grooteplein Zuid 10, 6525 GA Nijmegen
Country [2] 280915 0
Netherlands

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304132 0
Health and Disability Ethics Committees
Ethics committee address [1] 304132 0
Postal address:
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140

Street address:
133 Molesworth Street Thorndon, Wellington 6011
Ethics committee country [1] 304132 0
New Zealand
Date submitted for ethics approval [1] 304132 0
07/10/2019
Approval date [1] 304132 0
08/12/2019
Ethics approval number [1] 304132 0
Ethics committee name [2] 304135 0
Universitas Padjadjaran Ethics Committee
Ethics committee address [2] 304135 0
Jl. Prof Eykman No. 38 Bandung 40161
Ethics committee country [2] 304135 0
Indonesia
Date submitted for ethics approval [2] 304135 0
14/10/2019
Approval date [2] 304135 0
30/01/2020
Ethics approval number [2] 304135 0

Summary
Brief summary
This is a proof of principle randomised trial of BCG versus placebo in medical and nursing students in one hospital in Bandung, Indonesia, to prevent conversion of an Interferon Gamma Release Assay (IGRA; reflecting new M. tuberculosis infection) over 12 months following the commencement of clinical training. 150 students with IGRA and HIV negative results will be randomised to BCG vaccination/revaccination or placebo. They will be followed for 12 months with repeat IGRA test at 3, 6, 9, and 12 months. They will be given a logbook to record potential exposures to M. tuberculosis. The study will inform the final design of a full-randomised trial powered to detect a difference in IGRA conversion between arms. An interlocking immunological study will assess whether BCG vaccination/revaccination induces trained immunity in the students, with an extra sample taken at one month and three months post vaccination (n=100).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95922 0
Prof Philip Hill
Address 95922 0
Centre for International Health,
Department of Preventive and Social Medicine,
University of Otago Medical School,
PO Box 56, Dunedin 9054,
Country 95922 0
New Zealand
Phone 95922 0
+64 3 479 9462
Fax 95922 0
+64 3 479 7298
Email 95922 0
philip.hill@otago.ac.nz
Contact person for public queries
Name 95923 0
Lika Apriani
Address 95923 0
TB Working Group, Infectious Disease Research Centre
Faculty of Medicine Universitas Padjadjaran
Jl. Prof Eykman No. 38 Bandung 40161
Country 95923 0
Indonesia
Phone 95923 0
+62 22 2044128
Fax 95923 0
Email 95923 0
lika.apriani@unpad.ac.id
Contact person for scientific queries
Name 95924 0
Philip Hill
Address 95924 0
Centre for International Health,
Department of Preventive and Social Medicine,
University of Otago Medical School,
PO Box 56, Dunedin 9054,
Country 95924 0
New Zealand
Phone 95924 0
+64 3 479 9462
Fax 95924 0
+64 3 479 7298
Email 95924 0
philip.hill@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a proof of principle trial (feasibility study), data collection and analysis will focus on acceptability, adverse events and completion of follow up and will not focus on hypothesis testing around primary endpoint for a larger trial.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
4151Study protocol    378216-(Uploaded-19-08-2019-18-00-46)-Study-related document.docx



Results publications and other study-related documents

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