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Trial registered on ANZCTR


Registration number
ACTRN12619000864123
Ethics application status
Approved
Date submitted
23/05/2019
Date registered
18/06/2019
Date last updated
18/06/2019
Date data sharing statement initially provided
18/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
POWER: Prevention with OM-85 of wheezing exacerbation recurrence trial..
Scientific title
POWER trial (Prevention with OM-85 of wheezing exacerbation recurrence trial): a double-blind randomised controlled trial of immunomodulation (with OM-85) in wheezing children.
Secondary ID [1] 297970 0
Nil known
Universal Trial Number (UTN)
Trial acronym
POWER trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
acute wheezing 312378 0
Condition category
Condition code
Respiratory 310936 310936 0 0
Asthma
Respiratory 311496 311496 0 0
Other respiratory disorders / diseases
Infection 311497 311497 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
OM-85 (Broncho Vaxom®)

OM-85 will be supplied as a capsule for children that contains 3.5mg of lyophilized bacterial lysates Haemophilus influenzae, Streptococcus (Diplococcus) pneumoniae, Klebsiella pneumoniae and K. ozaenae, Staphylococcus aureus, Streptococcus pyogenes and S. viridans (S. sanguinis), Moraxella (Branhamella/Neisseria) catarrhalis. Excipients of the capsule include (pregelatinised) corn starch, magnesium stearate, sodium glutamate (E621), mannitol, gelatin, antioxidant: propyl gallate (E310), colour, indigotine (E132). If the child has difficulty swallowing the capsule, the capsule can be opened and its contents can be poured into a drink (water, fruit juice, milk, breast milk etc.).

1 capsule of investigational product (OM-85) or placebo is to be taken orally on an empty stomach, daily for 10 days followed by 20 days no treatment, each month for 12 months, at least 6 weeks ±1week after visit 1 (recruitment during an acute wheezing episode).

Participants will be asked to return all capsule packets to investigators
Intervention code [1] 314505 0
Treatment: Drugs
Comparator / control treatment
Placebo

The placebo will be composed of the excipients of the capsules without the active substance.
This will include the (Pregelatinised) corn starch, magnesium stearate, sodium glutamate (E 621), mannitol, gelatine, antioxidant: propyl gallate (E 310), colour: indigotine (E 132), titanium dioxide (E171).
Control group
Placebo

Outcomes
Primary outcome [1] 320093 0
The total number of respiratory exacerbations over 12 months from the start of treatment. This will be assessed using weekly electronic dairy entries that will be completed by parents of children participating in the study.
Timepoint [1] 320093 0
12 months from the start of treatment
Primary outcome [2] 320094 0
Time from recruitment (during a respiratory exacerbation) to subsequent respiratory exacerbation within the 12 month follow-up.
This will be assessed using weekly electronic dairy entries that will be completed by parents of children participating in the study.
Timepoint [2] 320094 0
Number of days to the next respiratory exacerbation over 12 months after the beginning of treatment.
Secondary outcome [1] 370517 0
Exploratory outcome:
Identification of key immune pathways integral to the response to OM-85. This will be assessed using RNAseq analysis of whole blood and/or PBMC (peripheral blood mononuclear cells) as well as nasal epithelial cells.
Timepoint [1] 370517 0
Number of days until the unscheduled visit following the start of treatment. Samples collected at recruitment (Visit 1) [at least one month prior to intervention commencement] and when children attend a visit for a subsequent exacerbation (Unscheduled visit - at least one month after Baseline Visit 2 [when intervention begins]).
Number of days between start and finish of treatment. Samples collected at Baseline Visit 2 [when intervention begins] and Final Visit 4 [12 months post-intervention commencement]).

Eligibility
Key inclusion criteria
1. Male or female children 1-5.99 years of age presenting to PCH ED or QCH ED with a diagnosis of either: acute asthma; wheeze, no specific trigger; virus-induced wheeze; allergen-induced wheeze; exercise-induced wheeze; bronchiolitis; viral respiratory infection; reactive airways disease or lower respiratory tract infection (LTRI) by the treating physician.
2. Current wheeze as assessed by the treating physician or study investigators.
3. Parent(s) or legal guardian(s) of the child is able to understand the study requirements and willing to provide informed consent
Minimum age
1 Years
Maximum age
6 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known (or evidence of) chronic underlying condition (other than asthma)
2. Currently taking OM-85
3. Known adverse reaction or hypersensitivity to the active substance (bacterial lysates) or to any of the excipients in OM-85 in accordance with the composition.
4. History of malignancy
5. History of a prior diagnosis with cardiovascular disease or an arterial thromboembolic event
6. Treatment with immunosuppressant drugs including methotrexate, cyclosporine or azathioprine within 30 days prior to enrolment in this study
7. Any clinically relevant abnormal findings in physical examination and/or vital signs at Visit 1, which, in the opinion of the investigator, may deem the child unsuitable for the study.

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)
numbered kits allocated by the Pharmacy who are the holder of the allocation schedule.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
We used an electronic tool from the website called Randomization.com to generate the randomization sequence ( link: https://gdallal.pages.tufts.edu/randomize.htm).
The allocation of active to placebo subjects was 2:1. The total number of medication kits prepared was 258 kits which comprised 172 active medication kits and 86 placebo kits. The randomization tool was programmed to create 28 blocks of 9 numbers where 6 of the 9 allocation numbers were for active treatment and 3 of the 9 allocation numbers were for placebo treatment. A final block of 6 numbers was created and 4 of the 6 allocation numbers were for active treatment and 2 of the 6 allocation numbers were for placebo treatment.
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
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
For data analysis of the clinical trial intention to treat strategy will be employed. The primary aim of the study is to compare the number of wheezing attacks between the intervention and placebo group following the beginning of treatment. We used a straightforward method, simulation T tests for two means for the power and sample size estimation. Consistently we will use a permutation test to compare the means between the two groups.
The number of wheezing attacks in 12 months is a count variable. Poisson and negative binomial regression will be employed to estimate the incidence rate ratio (IRR) in the intervention versus placebo groups.
We will record the time from 1-month post recruitment (the baseline visit) to the first subsequent respiratory exacerbation. Survival curve analysis and Cox regression will be used for the time to event outcome variable.
We will also have binary outcome variables such as yes or no for viral infection and yes or no for human rhinovirus C infection. Logistic regression model will be employed to estimate odds ratios between the two groups.
Covariates such as age and gender will be include in all regression analyses.

Analysis (Part II – Mechanistic Systems Biology Analysis):

We aim to use multi-omic (systems biology) measurements to elucidate the specific mechanisms of action of OM-85 on the immune system of children with a history of acute wheeze. Preliminary exploratory analysis will rely on multivariate covariance projection methods designed to extract a small number of common latent components that maximise the covariance between omic data blocks (transcriptome, metabolome, microbiome) in relation to changes observed after administration of OM-85. Methods to be investigated include OnPLS (Lofstedt T, Trygg J. OnPLS - a novel muliblock method for the modelling of predictive and orthogonal variaion. Chemometrics. 2011;25:441-5.). Multi-block Component Analysis, Regularized Generalized Canonical Correlation Analysis (De Roover K, Ceulemans E, Timmerman ME. How to perform multiblock component analysis in practice. Behavior research methods. 2012;44(1):41-56 and Tenenhaus A, Tenenhaus M. Regularized generalized canonical correlation analysis for multiblock or multigroup data analysis. European Journal of Operational Research. 2014;238:391-403.). By comparing multiple methods, a consensus view of candidate biomarkers will be defined whilst avoiding algorithm bias. These methods will uncover candidate biomarkers related to viral infection and acute wheeze that can then be combined with other clinical measurements into a linear multilevel random-effects model, from which OM-85 BV’s longitudinal mechanistic effects can be predicated with statistical confidence.
Analysis (Part III – immunological biomarkers):
We will have many continuous outcome variables such as immunological biomarkers. After log transforming to approximate a normal distribution we will analyse these outcomes using T tests, ANOVA and linear regression, wherever appropriate. Some immunological biomarkers will be measured at several time points in the cohort and thus, generalized estimating equation techniques will be employed for the data analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2019
Actual
Date of last participant enrolment
Anticipated
30/06/2022
Actual
Date of last data collection
Anticipated
15/08/2023
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,WA
Recruitment hospital [1] 13765 0
Perth Children's Hospital - Nedlands
Recruitment hospital [2] 13766 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 26515 0
6009 - Nedlands
Recruitment postcode(s) [2] 26516 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 302492 0
Government body
Name [1] 302492 0
National Health and Medical Research Council
Country [1] 302492 0
Australia
Primary sponsor type
University
Name
the University of Western Australia
Address
35 Stirling Hwy
Crawley WA 6009 Australia
Country
Australia
Secondary sponsor category [1] 302394 0
None
Name [1] 302394 0
Address [1] 302394 0
Country [1] 302394 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303150 0
Child and Adolescent Health Service Human Ethics Committee
Ethics committee address [1] 303150 0
Level 5, Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Ethics committee country [1] 303150 0
Australia
Date submitted for ethics approval [1] 303150 0
Approval date [1] 303150 0
12/12/2018
Ethics approval number [1] 303150 0
RGS#1313

Summary
Brief summary
The proposed project aims to show that immunomodulation (IM) using a bacterial lysate can deviate the immune system towards more natural responses and away from those that lead to wheeze and do this by reprogramming key response pathways. We plan to use a state-of-the-art, systems biology methodology to precisely identify the responses involved as the basis of establishing IM as a safe, practical and scientifically-sound therapy. We will recruit “high-risk” wheezing preschool children and give a 12 months course of bacterial lysate with the inclusion of a placebo arm so that we can accurately determine how bacterial lysates perturb these responses. To ensure that the immunological data relate to a clinically relevant change, the study is designed to achieve a parallel clinical outcome. The knowledge this project will obtain is essential to understand how current IM agents deviate the immune system away from responses leading to wheeze and asthma. In turn, this information is essential to allow this field of research to develop to improve health translation by identifying the key regulatory checkpoints that can be targeted for novel asthma therapies as well as the development of more focused and efficient IM preparations with potentially permanent effects.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92650 0
Prof Peter Le Souef
Address 92650 0
Professor of Paediatrics
Consultant Respiratory Paediatrician
Level 5, Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 92650 0
Australia
Phone 92650 0
+61 (0)8 6456 5568
Fax 92650 0
Email 92650 0
[email protected]
Contact person for public queries
Name 92651 0
Ingrid Laing
Address 92651 0
Senior Research Fellow
Telethon Kids Institute
Level 7 West, Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 92651 0
Australia
Phone 92651 0
+61 (0)8 6319 1828
Fax 92651 0
Email 92651 0
[email protected]
Contact person for scientific queries
Name 92652 0
Ingrid Laing
Address 92652 0
Senior Research Fellow
Telethon Kids Institute
Level 7 West, Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 92652 0
Australia
Phone 92652 0
+61 (0)8 6319 1828
Fax 92652 0
Email 92652 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


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
No additional documents have been identified.