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Trial registered on ANZCTR


Trial ID
ACTRN12612000196842
Ethics application status
Approved
Date submitted
7/02/2012
Date registered
15/02/2012
Date last updated
30/08/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A maternal probiotic intervention for infant allergic disease prevention
Scientific title
A randomized placebo controlled trial of the effects of the probiotic Lactobacillus rhamnosus HN001 taken from the 1st trimester of pregnancy till 6 months post partum, if breastfeeding, on the development of eczema and atopic sensitization in infants by age 12 months.
Secondary ID [1] 279863 0
Nil
Universal Trial Number (UTN)
U1111-1127-9128
Trial acronym
PIP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Eczema in infants 285765 0
Atopic sensitization in infants 285766 0
Gestational diabetes mellitus 285767 0
Bacterial vaginosis during pregnancy 285768 0
Group B strep during pregnancy 285769 0
Condition category
Condition code
Skin 285942 285942 0 0
Dermatological conditions
Inflammatory and Immune System 285943 285943 0 0
Allergies
Reproductive Health and Childbirth 285944 285944 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Lactobacillus rhamnosus HN001 administered daily as capsules to women from 14-16 weeks gestation till 6 months post birth while breastfeeding. The starting viable cell number is 6.1x1010 CFU* per gram, which equates to a dose per capsule of 9.2x109 CFU.
Intervention code [1] 284189 0
Prevention
Comparator / control treatment
The placebo will be identical in appearance and smell and contain multodextran only
Control group
Placebo

Outcomes
Primary outcome [1] 286431 0
* Eczema defined according to the UK Working Party's Diagnostic Criteria for atopic dermatitis, which will be modified for use in infants. The criteria will be a history of scratching or rubbing plus 2 or more of the following occuring between birth and 1 year 1. a history of involvement of lower arms or legs 2. a history of a generally dry skin 3. visible eczema present on the cheeks or lower arms or legs with no axillary involvement - (to be assessed by study nurse at age 6 and 12 months)
Timepoint [1] 286431 0
Infant at age 6 and 12 months.
Primary outcome [2] 286432 0
Atopic sensitization using skin prick tests to common environmental and food allergens
Timepoint [2] 286432 0
Infant at age 12 months
Primary outcome [3] 286487 0
Eczema severity measured using SCORAD
Timepoint [3] 286487 0
Infant at age 6 and 12 months.
Secondary outcome [1] 295883 0
Gestational diabetes mellitus - defined using a gestational tolerance test where a fasting plasma glucose >=5.1 mmol/l or 1 hour post 75g glucose load >=10mmol/l or 2 hour post 75g glucose load of >=8.5 mmol/l is considered diagnostic.
Timepoint [1] 295883 0
Measured once only at 26-28 weeks gestation among women who do not have pre-existing diabetes. However women who have a clinical assessment of blood glucose between 20 and 26 weeks gestation and are positive for gestional diabetes, for safety reasons, will not be retested at 26-28 weeks but they will be included in a separate analysis.
Secondary outcome [2] 295884 0
Bacterial vaginosis will be based on a self-collected vaginal swab and assessed according to Nugent Score, with a score of 7-10 considered positive
Timepoint [2] 295884 0
Baseline measurements will be taken once only at 14-16 weeks gestation and outcomes measured once only at 35-37 weeks gestation.
Secondary outcome [3] 295885 0
Group B strep will be based on a self-collected vaginal/rectal swab and cultured to determine its presence or absence.
Timepoint [3] 295885 0
Baseline measurements will be taken once only at 14-16 weeks gestation and outcomes measured once only at 35-37 weeks gestation.
Secondary outcome [4] 295886 0
Samples of post colostrem breast milk will be self collected by mothers. Levels of the cytokines TGF-Beta 1 and TGF-Beta 2 will be analysed with a luminex cytokine kit, and IgA will be assessed using a total IgA ELISA kit, as per manufacturers instructions.
Timepoint [4] 295886 0
[4]* Once only in mothers at 3-7 days post birth
Secondary outcome [5] 295887 0
Maternal anthropometric measures (weight, height, head circumference, waist circumference) using nurses to apply standard methods recommended by the World Health Organisation.
Timepoint [5] 295887 0
Baseline measurements of weight, height, head and waist circumferences will be taken once at 14-16 weeks gestation. Weight and waist circumference only will be measured up to 3 times at 3-7 days, 6 and 12 months post birth as outcomes.
Secondary outcome [6] 296001 0
Infant anthropometric measures (weight, length, head circumference)
Timepoint [6] 296001 0
Up to 3 times at 3-7 days post birth, 6 months and 12 months post birth.
Secondary outcome [7] 300489 0
Faecal sample for the determination of gut microbiota type and function
Timepoint [7] 300489 0
Once only at 26-28 weeks gestation
Secondary outcome [8] 300490 0
Fasting lipids, SCFA and bile acids, gastric inhibitory peptide (GIP) and glucagon like peptide 1 (GLP-1) and Peptide YY in fasting blood.
Timepoint [8] 300490 0
Once only at 26-28 weeks gestation
Secondary outcome [9] 306843 0
Cord blood will be collected and prepared for storage for 1. later measurement of selected cytokines IFN-gamma , IL10, IL4, IL13, IL12, TGF-beta, TNF-alpha, and TNF-gamma and 2. later metabolomic analyses.
Timepoint [9] 306843 0
Once only at birth, collected by midwives.
Secondary outcome [10] 306844 0
Cord tissue will be collected and prepared for storage for later epigenetic analysis
Timepoint [10] 306844 0
Once only at birth, collected by midwives.
Secondary outcome [11] 310076 0
Infant faecal sample for determination of gut microbiota and function
Timepoint [11] 310076 0
Once only at age 12 months.
Secondary outcome [12] 310077 0
Infant skin swabs from two sites, one typical of eczema in infants (the neck) and one where eczema is uncommon (the armpit). The microbiota from the swabs will be analysed in relation to the presence of eczema. The effect of the study probiotic on this relationship will also be analysed.
Timepoint [12] 310077 0
Once only at age 12 months
Secondary outcome [13] 310078 0
Buccal swabs for genotyping and epigenetic analysis.
Timepoint [13] 310078 0
Once only at age 12 months
Secondary outcome [14] 317672 0
Maternal post natal depression at 1-2 months post partum using 10 questions from the Edinburgh Postnatal Depression Scale and 7 questions from the State Anxiety Inventory plus medication questions. To be self completed retrospectively.
Timepoint [14] 317672 0
For those infants still in the study, this will be completed using a hard copy questionnaire at age 6 or 12 months. For infants who have completed the study this will be completed electronically at age 12-30 months.

Eligibility
Key inclusion criteria
A woman will be eligible if 1. either they or the unborn child’s biological father has a history of asthma or eczema treated by a doctor or allergic rhinitis treated by a doctor or pharmacist (but excluding alternative, herbal or homeopathic medicine). 2. she is 14 to 16 weeks gestation 3. she intends to breastfeed 4. she speaks English
Minimum age
16 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
A woman will be ineligible if she
1. has a serious immunological disorder or is using immunomodulatory drugs
2. is currently using or intends to use probiotic drinks or supplements in themselves or in their child
3. is participating in another RCT
4. has known cardiac vavle disease for which antibiotic prophylaxis is required if undergoing dental procedures
5. required IVF to establish this pregnancy
6. has a pre-enrolment scan showing fetal abnormalities
7. does not agree to GP, midwife or hospital staff notification
8. has a severe allergy to cow's milk that requires her to carry adrenalin
9. has a history of transplant
10. has a history of HIV
11. is on continuous long-term antibiotics
12. does not intend to stay in Wellington or Auckland for the next 18 months
13. has miscarried since screening but prior to enrolment 14. is deemed unsuitable for study inclusion

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)
The reseach staff will determine eligibility prior to allocation of the woman into study group and remain blinded throughout the study. The bottles will be numbered off site. Research staff will will select the next available number to allocate at enrolment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be stratifed by study center (Auckland/Wellington) in blocks using a computer generated randomisation list.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
1. An intention-to-treat analysis will be used to assess the effect of L. rhamnosus (HN001) on the 12 month cumulative prevalence of eczema and SCORAD greater than or equal to 10 using hazard ratios, and the point prevalence of atopy at age 12 months, using relative rate.
2. Chisq test will also be used to compare the proportion in each study group with detectable levels of each cytokine and immunological marker in breast milk and cord blood and for those with detectable levels, t-tests will be used to compare the groups if the data is log-normally distributed. If the data is not log-normally distributed a Wilcoxon Rank Sum test will be used.
3. The association of L. rhamnosus (HN001) with the presence of gestational diabetes mellitus, bacterial vaginosis and Group B Strep will be assessed using relative rate.
4. The effect of weight gain will be investigated as an intermediate variable by adding it to the model in the GDM analysis.

Power calculation
From our previous study the hazard ratio for eczema, for L rhamnosus HN001, based on the data at 6 and 12 months, was 0.39, with 12.3% of people having eczema at either 6 or 12 months. With a sample size of 400 and 13% drop out rate 42.8 babies are expected to be assessed as having eczema. Using the sample size formula from Therneau and Grambsch ‘Modeling Survival Data’ 2000 Springer, the study would have 87% power.

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
Current
Final
Recruitment outside Australia
Country [1] 4102 0
New Zealand
State/province [1] 4102 0

Funding & Sponsors
Funding source category [1] 284640 0
Government body
Name [1] 284640 0
Health Research Council New Zealand
Address [1] 284640 0
PO Box 5541, Wellesley Street, Auckland 1141
Country [1] 284640 0
New Zealand
Primary sponsor type
Individual
Name
Dr Kristin Wickens
Address
Wellington Asthma Research Group
Department of Medicine
Wellington School of Medicine and Health Sciences
University of Otago
P O Box 7343
Wellington South 6242
Country
New Zealand
Secondary sponsor category [1] 283553 0
Individual
Name [1] 283553 0
Professor Julian Crane
Address [1] 283553 0
Wellington Asthma Research Group
Department of Medicine
Wellington School of Medicine and Health Sciences
University of Otago
P O Box 7343
Wellington South 6242
Country [1] 283553 0
New Zealand
Other collaborator category [1] 260504 0
Individual
Name [1] 260504 0
Dr Thorsten Stanley
Address [1] 260504 0
Department of Paediatrics
Wellington School of Medicine and Health Sciences
University of Otago
Wellington South
Country [1] 260504 0
New Zealand
Other collaborator category [2] 260505 0
Individual
Name [2] 260505 0
Dr Edwin Mitchell
Address [2] 260505 0
Department of Paediatrics
University of Auckland
Room 029, Level 12, Support Bldg
Auckland City Hospital, Park Rd
Grafton
Auckland 1142
Country [2] 260505 0
New Zealand
Other collaborator category [3] 260506 0
Individual
Name [3] 260506 0
Dr Peter Abels
Address [3] 260506 0
Department of Obstetrics and Gynaecology
University of Otago
Wellington
Country [3] 260506 0
New Zealand
Other collaborator category [4] 260507 0
Individual
Name [4] 260507 0
Ms Christine Barthow
Address [4] 260507 0
Wellington Asthma Research Group
Department of Medicine
Wellington School of Medicine and Health Sciences
University of Otago
P O Box 7343
Wellington South 6242
Country [4] 260507 0
New Zealand
Other collaborator category [5] 260508 0
Individual
Name [5] 260508 0
Dr Penny Fitzharris
Address [5] 260508 0
Department of Immunology
Auckland Hospital
Grafton Rd
Grafton
Auckland 1142
Country [5] 260508 0
New Zealand
Other collaborator category [6] 260509 0
Individual
Name [6] 260509 0
Mr Gordon Purdie
Address [6] 260509 0
Department of Public Health
University of Otago
Mein St
Newtown
Wellington 6242
Country [6] 260509 0
New Zealand
Other collaborator category [7] 260510 0
Individual
Name [7] 260510 0
Ms Robyn Maude
Address [7] 260510 0
Graduate School of Nursing and Midwifery
Victoria University of Wellington
Mein St
Newtown
Wellington 6242
Country [7] 260510 0
New Zealand
Other collaborator category [8] 277236 0
Individual
Name [8] 277236 0
Professor Peter Stone
Address [8] 277236 0
School of Medicine
The University of Auckland
Private Bag 92019 Auckland
Country [8] 277236 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286633 0
Multiregion Ethics Committee
Ethics committee address [1] 286633 0
Ministry of Health
No 1 The Terrace
PO Box 5013
Wellington 6011
Ethics committee country [1] 286633 0
New Zealand
Date submitted for ethics approval [1] 286633 0
Approval date [1] 286633 0
19/10/2011
Ethics approval number [1] 286633 0
MEC/11/09/077

Summary
Brief summary
The increase in allergic disease among children in the developed world is widely believed to be due to reductions in exposure to infective agents (the hygiene hypothesis). One way to counteract this is by exposing pregnant women to beneficial bacteria, such as probiotics. Using a randomized controlled double-blinded trial, we aim to investigate the effect of L rhamnosus HN001 taken daily (9X10^9 CFU) by pregnant women from the first trimester of pregnancy and during breast feeding until 6 months post-partum on the development of eczema and atopic sensitization in their infants at age 12 months. The effects of this probiotic on maternal health in pregnancy, including gestational diabetes mellitus, group B streptococcal vaginal infection and bacterial vaginosis will also be investigated as secondary outcomes. Probiotics are a cheap and safe intervention that may prevent cases of eczema and allergy in infancy and improve pregnancy outcomes for women.
Trial website
www.otago.ac.nz/probiotic
Trial related presentations / publications
1. Barthow C, Wickens K, Stanley T, et al. (2016) The Probiotics in Pregnancy Study (PiP Study): rationale and design of a double-blind randomised controlled trial to improve maternal health during pregnancy and prevent infant eczema and allergy. BMC Pregnancy and Childbirth DOI: 10.1186/s12884-016-0923-y
Public notes

Contacts
Principal investigator
Name 33727 0
Dr Kristin Wickens
Address 33727 0
Wellington Asthma Research Group
Wellington School of Medicine and Health Sciences
University of Otago
P O Box 7343
Wellington South
Wellington]
New Zealand
Country 33727 0
New Zealand
Phone 33727 0
0064 4 918 6780
Fax 33727 0
0064 4 389 5427
Email 33727 0
kristin.wickens@otago.ac.nz
Contact person for public queries
Name 16974 0
Prof Professor Julian Crane
Address 16974 0
Wellington Asthma Research Group
Wellington School of Medicine and Health Sciences
University of Otago
P O Box 7343
Wellington South 6242
Country 16974 0
New Zealand
Phone 16974 0
+64 04 918 5258
Fax 16974 0
+64 4 389 5427
Email 16974 0
julian.crane@otago.ac.nz
Contact person for scientific queries
Name 7902 0
Dr Dr Kristin Wickens
Address 7902 0
Wellington Asthma Research Group
Wellington School of Medicine and Health Sciences
University of Otago
P O Box 7343
Wellington South 6242
Country 7902 0
New Zealand
Phone 7902 0
+64 04 918 6780
Fax 7902 0
+64 4 389 5427
Email 7902 0
kristin.wickens@otago.ac.nz