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Trial registered on ANZCTR


Registration number
ACTRN12618000150246
Ethics application status
Approved
Date submitted
26/01/2018
Date registered
1/02/2018
Date last updated
9/02/2022
Date data sharing statement initially provided
9/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
PneuMatters: maternal immunisation to prevent pneumonia in children
Scientific title
A multi-centre, observer blinded, randomised controlled trial to evaluate the efficacy of the 10 valent pneumococcal-Protein D conjugate (PHiD-CV) vaccine administered during pregnancy in preventing acute lower respiratory infection (ALRI) in Australian Indigenous and Malaysian infants up to 12 months of age, compared to infants whose mothers were not vaccinated in pregnancy.
Secondary ID [1] 293886 0
NHMRC APP 1138555
Universal Trial Number (UTN)
U1111-1208-5603
Trial acronym
PneuMatters
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Acute Lower Respiratory Infection 306355 0
Condition category
Condition code
Respiratory 305443 305443 0 0
Other respiratory disorders / diseases
Infection 305462 305462 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Pneumococcal polysaccharide conjugate vaccine, 10 valent adsorbed, 1 dose of 0.5mls administered intramuscularly to pregnant women between 28 - 34 weeks gestation. The vaccine will be administered by an accredited nurse immuniser.
Intervention code [1] 300156 0
Prevention
Comparator / control treatment
Controls receive no intervention
Control group
Active

Outcomes
Primary outcome [1] 304579 0
Incidence rate of medically attended acute respiratory infections in infants. Endpoint case definition of ALRI is a medically attended episode of illness defined as the presence of acute cough, dyspnoea, raised respiratory rate for age, new abnormal chest exam findings or radiographic findings for presumed respiratory illness. Clinic visits for ALRIs within 2 weeks of each other will be counted as part of the same ALRI. Outcome assessed by parent report and medical record review.
Timepoint [1] 304579 0
12 months of age
Secondary outcome [1] 342439 0
Local and systemic adverse events following vaccination in pregnancy. These will be collected via standard vaccine trial diary cards and in accordance with the Global Alignment of Immunization Safety Assessment in Pregnancy Guidelines and criteria.
Timepoint [1] 342439 0
30 days post vaccination
Secondary outcome [2] 342440 0
Serious vaccine-related adverse events in pregnancy and childbirth. These will be collected and assessed in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines and the Global Alignment of Immunization Safety Assessment in Pregnancy Guidelines and criteria.
Timepoint [2] 342440 0
Any time point up to childbirth
Secondary outcome [3] 342441 0
Serious vaccine-related adverse events in the infant. These will be collected and assessed in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines and the Global Alignment of Immunization Safety Assessment in Pregnancy Guidelines and criteria.
Timepoint [3] 342441 0
Any time up to 12 months of age
Secondary outcome [4] 342442 0
Vaccine type antibody responses (serum IgGs) - Total IgG to both Protein D and vaccine-type S. pneumoniae. This will be undertaken in a subgroup of infants.
Timepoint [4] 342442 0
Maternal at baseline and birth
Infant at birth, 6 months and 12 months of age
Secondary outcome [5] 342443 0
Infant systemic immune responses (TNF-alpha, IFN-y, IL-6, IL-13, IL-1beta) from peripherical blood mononuclear cells (PBMC). Briefly, PBMC (1x106 cells/ml) will be challenged with live NTHi or Spn (4x106 colony forming units/ml), phyto-hemagglutinin (PHA; positive control) or medium alone (baseline control). Cytokine protein, representative of innate response (TNF-a), Th1- (IFN-gamma) and Th2-immune response (IL-6, IL-13) and inflammation regulation (IL-1ß,) will be measured in culture supernatants at 24 or 72 hours. This will only be undertaken in a subset of infants.
Timepoint [5] 342443 0
At 12 months
Secondary outcome [6] 342444 0
Nasopharyngeal carriage of Haemophilus influenzae and Streptococcus pneumoniae. Batches of swabs will be thawed and cultured on selective media. Growth of Spn (with serotypes determined), Hi and NTHi will be confirmed by standard techniques, including differentiating from H. haemolyticus
Timepoint [6] 342444 0
Maternal: baseline and birth
Infant: birth, 6 and 12 months of age
Secondary outcome [7] 406066 0
Proportion of children with any medically attended ALRIs. Assessed by parent report and medical record review.
Timepoint [7] 406066 0
12 months of age
Secondary outcome [8] 406067 0
Time in days from birth to first medically attended ALRI. This will be assessed by calculating the number of days from birth to the date of the medical review as recorded in medical records.;
Timepoint [8] 406067 0
by 12 months of age.
Secondary outcome [9] 406068 0
Pneumonia (confirmed by chest x-ray and clinically defined) and hospitalised ALRI episodes, with and without antibiotics. Assessed by medical record review
Timepoint [9] 406068 0
By 12 months of age

Eligibility
Key inclusion criteria
(1) Infant to be identified as Aboriginal and/or Torres Strait Islander, Maori/Pacific Islander or Malaysian
(2) Generally healthy women aged 17-40 years
(3) Singleton pregnancy at 27 weeks (plus 6 days) to 34 weeks (plus 6 days) gestation at time of randomisation;
(4) Treating obstetrician/medical practitioner managing the pregnancy approves participant’s enrolment in the study
(5) Provision of written informed consent and willing and able to meet the requirements of the protocol
(6) Planned delivery at one of the study hospitals and
(7) Not planning to move from the study area before the infant turns 12 months of age
Minimum age
17 Years
Maximum age
40 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Considered to be high-risk pregnancy* by attending obstetrician
2. Receipt of any pneumococcal vaccine in the 2 years prior to randomisation
3. Contraindication or known hypersensitivity to 10vPHiD-CV as per the Australian Immunisation Handbook
4. Confirmed or suspected immunosuppressive condition or immunodeficiency disorder that can be expected to interfere with immune responses to vaccination;
5. Current (or within 90 days prior to receiving study vaccine) or planned (during the active study period) immunosuppressive therapy, including systemic corticosteroids (for 14 of more days in a 30-day period);
6. Administration of immunoglobulins and/or blood products, with the exception of Rh Immune Globulin, within 90 days prior to receiving study vaccine, or planned administration of such products during the study period;
7. Active participation in a clinical trial of another investigational drug/vaccine or interventional therapy.
8. Other medical/psychosocial condition that the investigators/treating physicians consider should be excluded from the trial to prevent potential harm/risk to the subject or may adversely affect study outcomes.
*Refers to a list of high-risk conditions considered ineligible. Final decision on conditions not on the list to be made by treating obstetrician/medical practitioner.

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)
Central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The random treatment allocation will be computer-generated, stratified (permuted blocks and by site), concealed and supervised by the trial biostatistician
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Outcome assessors and data analysts will be blinded to the allocation group
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
For primary aim: The main effects of the intervention will be determined by comparing the primary outcome (rate of ALRI); in the first year of life between groups (PHiD-CV group vs controls). We will report incidence rate ratio ((with 95%CI) using negative binomial regression model.

Sensitivity analyses will be performed by ALRI classification (ie ALRI case-definition confirmed, medically attended respiratory illness case-definition not confirmed, parent reported respiratory illness, and ALRIs episodes with/without antibiotics prescribed). We plan a preliminary analysis when 50% of the sample size for primary outcomes are available at 6-mo. We plan a 6-month analysis (rather than at 12-months, our RCT’s outcome) for safety reasons,

For secondary lab outcomes: We will compare differences between groups in: (i) IgGs geometric means of PD23 and serotype-specific Spn16 using Student’s T test after log transforming data (+/- maternal prevaccine levels adjustment); (ii) cytokine levels of PBMC-stimulated cells (Mann-Whitney23,47); (iii) NP Hi and Spn (vaccine and non-vaccine types separated) using Chi2 expressed as OR (95%CI).

For ALRI outcomes: A Kaplan-Meier curve will be constructed for each group for time to the 1st ALRI and respiratory-related hospitalisation, log-rank test performed and hazard ratio reported (using Cox regression model).

We will also analyse results based on the different definitions of ALRIs (pneumonia confirmed by chest x-ray and clinically defined] and hospitalised ALRI episodes, with and without antibiotics).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/09/2018
Actual
14/01/2019
Date of last participant enrolment
Anticipated
30/08/2023
Actual
Date of last data collection
Anticipated
30/08/2024
Actual
Sample size
Target
292
Accrual to date
110
Final
Recruitment in Australia
Recruitment state(s)
NT,QLD
Recruitment hospital [1] 9876 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [2] 9877 0
Toowoomba Hospital - Toowoomba
Recruitment hospital [3] 9878 0
Logan Hospital - Meadowbrook
Recruitment hospital [4] 21672 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 21673 0
Darwin Private Hospital - Tiwi
Recruitment hospital [6] 21674 0
Palmerston Regional Hospital - Holtze
Recruitment postcode(s) [1] 18680 0
4350 - Toowoomba
Recruitment postcode(s) [2] 18681 0
4131 - Meadowbrook
Recruitment postcode(s) [3] 36719 0
4029 - Herston
Recruitment postcode(s) [4] 36720 0
0810 - Tiwi
Recruitment postcode(s) [5] 36721 0
0829 - Holtze
Recruitment outside Australia
Country [1] 9526 0
Malaysia
State/province [1] 9526 0
Kota Kinabalu

Funding & Sponsors
Funding source category [1] 298509 0
Government body
Name [1] 298509 0
National Health & Medical Research Council
Country [1] 298509 0
Australia
Primary sponsor type
University
Name
Menzies School of Health Research
Address
Rocklands Drive
TIWI NT 0811
Country
Australia
Secondary sponsor category [1] 297655 0
None
Name [1] 297655 0
Address [1] 297655 0
Country [1] 297655 0
Other collaborator category [1] 279917 0
University
Name [1] 279917 0
Queensland University of Technology
Address [1] 279917 0
Musk Ave
Kelvin Grove QLD 4059
Country [1] 279917 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299488 0
Menzies School of Health Research Health Research Ethics Committee
Ethics committee address [1] 299488 0
Menzies School of Health Research
Rocklands Drive
TIWI NT 0811
Ethics committee country [1] 299488 0
Australia
Date submitted for ethics approval [1] 299488 0
05/03/2018
Approval date [1] 299488 0
31/07/2018
Ethics approval number [1] 299488 0
2018-3128
Ethics committee name [2] 310310 0
Metro South Hospital and Health Service HREC
Ethics committee address [2] 310310 0
L 7 Translational Research Institute
Woolloongabba QLD 4102
Ethics committee country [2] 310310 0
Australia
Date submitted for ethics approval [2] 310310 0
10/08/2018
Approval date [2] 310310 0
20/09/2019
Ethics approval number [2] 310310 0
HREC/2018/QMS/44099
Ethics committee name [3] 310311 0
Queensland University of Technology University Research Ethics Committee
Ethics committee address [3] 310311 0
Queensland University of Technology
Musk Ave
Kelvin Grove QLD 4059
Ethics committee country [3] 310311 0
Australia
Date submitted for ethics approval [3] 310311 0
21/08/2018
Approval date [3] 310311 0
11/10/2018
Ethics approval number [3] 310311 0
1800000848
Ethics committee name [4] 310312 0
The University of Queensland Medical Research Ethics Committee
Ethics committee address [4] 310312 0
Human Research Ethics Office
Cumbrae-Stewart Building #72
The University of Queensland
St Lucia, QLD, 4072
Ethics committee country [4] 310312 0
Australia
Date submitted for ethics approval [4] 310312 0
10/01/2019
Approval date [4] 310312 0
19/06/2019
Ethics approval number [4] 310312 0
2019000053

Summary
Brief summary
We plan a parallel, single-blind multicentre RCT (with concealed allocation) to determine the efficacy of maternal PHiD-CV immunisation on infant respiratory outcomes. Our primary question is: Does vaccinating pregnant Indigenous women with PHiD-CV (compared to controls) reduce ALRI in their infants in the first year of life? Our primary hypothesis is that: Infants born to pregnant women who received PCV-HiD have at least 30% less ALRIs in their first year of life, compared to those who did not receive the vaccine
Trial website
Nil to date
Trial related presentations / publications
Nil to date
Public notes
Nil to date

Contacts
Principal investigator
Name 80582 0
Prof Anne Chang
Address 80582 0
Menzies School of Health Research
Rocklands Drive
TIWI NT 0810
Country 80582 0
Australia
Phone 80582 0
+61 0411 699 022
Fax 80582 0
Email 80582 0
[email protected]
Contact person for public queries
Name 80583 0
Remai Mitchell
Address 80583 0
L7 Centre for Children's Health Research
62 Graham Street
South Brisbane QLD 4010
Country 80583 0
Australia
Phone 80583 0
+61 7 3069 7277
Fax 80583 0
Email 80583 0
[email protected]
Contact person for scientific queries
Name 80584 0
Remai Mitchell
Address 80584 0
L7 Centre for Children's Health Research
62 Graham Street
South Brisbane QLD 4010
Country 80584 0
Australia
Phone 80584 0
+61 7 3069 7277
Fax 80584 0
Email 80584 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are specific cultural issues around the sharing of data from Australian Aboriginal and Torres Strait Islander peoples. It is standard Menzies policy that IPD cannot be shared without individual approval from participants and we have not sought consent from the participants for this.


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
EmbaseStudy Protocol for Preventing Early-Onset Pneumonia in Young Children Through Maternal Immunisation: A Multi-Centre Randomised Controlled Trial (PneuMatters).2022https://dx.doi.org/10.3389/fped.2021.781168
N.B. These documents automatically identified may not have been verified by the study sponsor.