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Trial registered on ANZCTR


Registration number
ACTRN12615000402549
Ethics application status
Approved
Date submitted
9/04/2015
Date registered
30/04/2015
Date last updated
24/05/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Can one month of Bacteriocin Like Inhibitory Substances BLIS K12 Probiotic with Streptococcus Salivarius taken by Whakatane Primary School children prevent colonization with Group A Streptococcus (GAS) pathogens and decrease GAS Sore throats in this study.
Scientific title
For school pupils at risk of acute rheumatic fever, can one month of probiotic Salivarius BLIS K12 lessen Group A Streptococcal throat carriage and infection?
Secondary ID [1] 286502 0
Nil known
Universal Trial Number (UTN)
U1111-1168-0145
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Group A Streptococcal Throat colonization 294716 0
Group A Streptococcal Sore throats 294717 0
Condition category
Condition code
Infection 295004 295004 0 0
Studies of infection and infectious agents
Oral and Gastrointestinal 295051 295051 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Public Health 295052 295052 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The one month of probiotic Salivarius BLIS K12, the dose will be one tablet daily each with 2 x 10 to the 9th ( 2 x 100,000,000) colony forming units of S. Salivarius K12 plus the lyoprotectant agents trehalose, lactitol and maltodextrin, which are added to enhance the stability and viability of the bacteria. Blis K12 disolves in mouth,
and while disolving in mouth is preferred for efficacy, can be swallowed. Adherance will be monitored as the children are school pupils for the 5 weekdays witnessed by teachers and community health workers and observed for 2 days by their parents
Intervention code [1] 291596 0
Prevention
Comparator / control treatment
One school will receive no treatment initially. The BLISS K12 probiotic intervention will be offered to this school's pupils 4-6 weeks after the first two schools start the same intervention
Control group
Active

Outcomes
Primary outcome [1] 294759 0
The primary outcome is the Group A Streptococcal GAS throat colonization rate will be established comparing the number of positive GAS throat swabs taken by community health workers, compared with the total of all consented pupils who had a throat swab taken.
Timepoint [1] 294759 0
The primary time points for checking throat swabs are prior to commencing the probiotic, then one month after onset of probiotic use, then three and four month after onset of probiotic use
Secondary outcome [1] 313999 0
The secondary outcome is the Group A Streptococcal GAS Sore throat rate. It will be established comparing the number of children with BOTH positive GAS throat swabs and symptomatic sore throat on questioning whether their throat is sore or comfortable prior to the swab being taken by CHW compared with the total of all consented pupils who had a throat swab taken. The tool willl be the throat swab, the question about throat soreness or comfort and the record of that reply matching the throat swab taken.
Timepoint [1] 313999 0
The secondary time points will be just prior to the onset of the BLIS K12 trial then one month after onset of taking probiotic BLIS K12 for a month, with further secondary time points 3 and 4 month after onset of one month course of probiotic Blis K12.

Eligibility
Key inclusion criteria
All School pupils of consenting parents at three nominated primary schools
Minimum age
5 Years
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Pupils currently on BLIS K12, the children of non consenting parents, children with significant immunocompromise ( do not anticipate any but screening questions on consent address this possibility )

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
With a stepped wedge design, Two whole schools will be allocated to the treatment for a month to 6 weeks prior to the third school commencing. This will mean that the third schools' two pre treatment GAS swabs status in that period will be controls with no active treatment for that period. They will then have identical one month BLIS with completion, and three month after starting GAS swabs.
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
Parallel
Other design features
Two Geographically similar rural schools with similar demographics near 100% Maori pupils, will be assigned to the initially commencing and later commencing groups which limits the risk of confounding factors, accounting for assessed differences in Group A Streptococcal throat colonization rates. A third school Education quintile 1 but decile 2, with similar NZDeps in the initially begininng group is urban and has 75% Maori pupils. All schools have mainly Maori pupils and similar Education decile 1 meaning significantly likely to have families from NZ Deprivation centiles 8,9, 10 of the age group 5-12years the most vulnerable to GAS and complication of Acute Rheumatic fever.
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Firstly to test the primary outcome of BLIS K12 impact on “GAS carriage at one month”, the first two schools (whose pupils n250 start BLIS K12 first ) change in Group A Streptococcal GAS throat carriage or colonization rate ( asymptomatic positive swabs over total swabbed pupils) over the month of BLIS K12 treatment will be compared to the change in rate of the untreated ( yet to be treated) control group n250 of the third school .Our assumptions for the main outcome, 20% baseline carriage, 90% consent, 85% adherence, true effect size calculated at 86% initially with measured effect size 73% and expected carriage 5.4% we will be able to reject a null hypothesis of experimental and control rates being equal probability 0.997. An uncorrected chi –squared statistic will be used to evaluate this null hypothesis. If 80% consent and 61% efficacy the study will have 83.4% power hence still a well powered study.
Secondly to test the secondary outcome the GAS sore throat rate ( symptomatic sore throats on questioning that are GAS positive, divided by all throat swabs taken at that school) over the same period of the month of BLIS K12,will be compared between first two and third control “yet to start school”, comparing point prevalence of GAS sore throats. These two first comparisons also control for seasonal variation.
Having controlled for seasonal variation/documented how much is occuring in controls a third series of comparisons of rates will be made with n500 comparing GAS throat colonization rate (asymptomatic and symptomatic) before, after one month of intervention, 3 months after starting BLIS and for n 250 four months after starting BLIS; Fourthly comparisons of rates over time will compare GAS sore throat rate again with confidence intervals, p values.

Recruitment
Recruitment status
Completed
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 outside Australia
Country [1] 6799 0
New Zealand
State/province [1] 6799 0
Bay of Plenty

Funding & Sponsors
Funding source category [1] 291069 0
Other
Name [1] 291069 0
Eastern Bay Primary Health Alliance
Address [1] 291069 0
29-31 Richardson St
Whakatane
New Zealand 3020
Country [1] 291069 0
New Zealand
Primary sponsor type
Other
Name
Eastern Bay Primary Health Alliance
Address
29-31 Richardson St
Whakatane
New Zealand 3020
Country
New Zealand
Secondary sponsor category [1] 289749 0
Government body
Name [1] 289749 0
BOPDHB Bay of Plenty District Health Board
Address [1] 289749 0
Whakatane Hospital
Stewart St
POBox 241
Whakatane 3020
Country [1] 289749 0
New Zealand
Other collaborator category [1] 278429 0
Other Collaborative groups
Name [1] 278429 0
Te Tohu o Te Ora o Ngati Awa
Address [1] 278429 0
PO Box 2076 Kopeopeo
36 Thornton Road
Whakatane
3020
Country [1] 278429 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292652 0
HDEC Health and Disabiltiy Ethics Committee MOH Wellington
Ethics committee address [1] 292652 0
HDEC, Ministry of Health New Zealand
Ethics Department
Reception Ground Floor
20 Aitken Street Thorndon Wellington 6011
Ethics committee country [1] 292652 0
New Zealand
Date submitted for ethics approval [1] 292652 0
16/04/2015
Approval date [1] 292652 0
16/06/2015
Ethics approval number [1] 292652 0
15/CEN/51

Summary
Brief summary
We propose to offer a probiotic BLIS K12 to about 500 Whakatane primary school children. In small trials in Italy and Kawerau, NZ it has decreased acute Group A Streptococcal GAS sore throats and recurrent GAS sore throats respectively, both while taken and for many months to follow. Using an open stepped wedge design we will compare GAS colonization and point prevalence of GAS sore throats as our primary outcome measures; The yet to start school rates will be controls for the first month then participants
Trial website
Trial related presentations / publications
Bennett M, Wana L,Ball S, Malcolm J.(October 2014)BLIS K12 stops Kawerau Group A Strep School sore throats; Finalist presentation, Bay of Plenty District Health Board Clinical Research Awards,23/10/2014 BOPDHB Tauranga.

Ball S,Malcolm J,Hartley L,Wana L Bennett M,Ingram-Seal R, Stewart J,Lennon D.(March 2015).Pharyngeal Group A Streptococcal Throat Prevalence declines with school sore throat swabbing " Kiri ora" healthy skin programme and appears to parallel declining acute rheumatic fever; Poster presented at Australasian Society of Infectious Diseases ASM, Auckland NZ 19/3/2015.
Public notes
The first presentation refers to a local open trial of BLIS K12 n23 in recurrent GAS infections from which we derive the likely % change in GAS colonization and GAS sore throats for the power calculations.

The second study refers to the likely GAS colonization rate at the onset of our study 20%, based on our similar adjacent communities in this study of Kawerau similar demographics age, ethnicity and deprivation deciles.

Contacts
Principal investigator
Name 56410 0
Dr John Malcolm
Address 56410 0
Whakatane Hospital
PO BOX 241
Stewart St
Whakatane 3020
Country 56410 0
New Zealand
Phone 56410 0
+6473060999
Fax 56410 0
Email 56410 0
john.malcolm@bopdhb.govt.nz
Contact person for public queries
Name 56411 0
Dr John Malcolm
Address 56411 0
Whakatane Hospital
PO BOX 241
Stewart St
Whakatane 3020
Country 56411 0
New Zealand
Phone 56411 0
+6473060999
Fax 56411 0
Email 56411 0
john.malcolm@bopdhb.govt.nz
Contact person for scientific queries
Name 56412 0
Dr John Malcolm
Address 56412 0
Whakatane Hospital
PO BOX 241
Stewart St
Whakatane 3020
Country 56412 0
New Zealand
Phone 56412 0
+6473060999
Fax 56412 0
Email 56412 0
john.malcolm@bopdhb.govt.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary