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Trial registered on ANZCTR


Registration number
ACTRN12607000518460
Ethics application status
Approved
Date submitted
2/10/2007
Date registered
9/10/2007
Date last updated
30/11/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A trial of the effect of probiotics on the development of atopy and eczema in children
Scientific title
A trial of the effect of probiotics on the development of atopy and eczema in children
Secondary ID [1] 287313 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Eczema,
Atopy 2414 0
Condition category
Condition code
Skin 2520 2520 0 0
Dermatological conditions
Public Health 2521 2521 0 0
Epidemiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study interventions were the probiotics, Lactobacillus rhamnosus (10**9 colony forming units) and Bifidobacteria lactis (10**9 colony forming units) administered orally. In mothers this was taken daily from 35 weeks gestation till 6 months if breastfeeding. In infants this was administered daily from birth for 2 years.
Intervention code [1] 2137 0
Prevention
Comparator / control treatment
The placebo contained dextran, salt and a high quality refined yeast extract, developed to be similar in appearance and odour to the active intervention. In mothers this was taken daily from 35 weeks gestation till 6 months if breastfeeding. In infants this was administered daily from birth for 2 years.
Control group
Placebo

Outcomes
Primary outcome [1] 3417 0
Atopy was measured using skin prick tests.
Timepoint [1] 3417 0
At 24 mths, 4 yrs, 6 yrs and 11 yrs of age
Primary outcome [2] 3418 0
Eczema is defined according to the UK Working Party's Diagnostic Criteria for Atopic Dermatitis, modified for use in children under 2 years.
Timepoint [2] 3418 0
At age 3 mths, 6 mths, 12 mths, 18 mths, 24 mths, 4 yrs, 6 yrs and 11 yrs of age
Primary outcome [3] 295887 0
Specific and total IgE. After administration of topical anaesthesia, 3.5 ml of blood was sampled. Serum specific IgE (ssIgE) was analysed using the Phadia ImmunoCAP ssIgE fluorescence enzyme immunoassay (Phadia AB, Uppsala, Sweden). Total IgE was analysed using Roche Cobas e601 total IgE electrochemiluminescence immunoassy (Roche DiagnosticsGmbH, D-68298 Mannheim, Germany)
Timepoint [3] 295887 0
6 years
Secondary outcome [1] 5678 0
The presence of Lactobacillus populations in faecal samples
Timepoint [1] 5678 0
Birth, 3 mths, 12 mths and 24 mths
Secondary outcome [2] 5679 0
The presence of Bifidobacteria populations in faecal samples
Timepoint [2] 5679 0
Birth, 3 mths, 12 mths and 24 mths
Secondary outcome [3] 5708 0
SCORAD - A standardised method of scoring eczema severity
Timepoint [3] 5708 0
At age 3 mths, 6 mths, 12 mths, 18 mths, 24 mths, 4 yrs, 6 yrs of age
Secondary outcome [4] 316829 0
Parental reported asthma, wheeze, rhinitis in child using modified standard questions from the International Study of Asthma and Allergies in Childhood questionnaires.
Timepoint [4] 316829 0
6 and 11 years
Secondary outcome [5] 316830 0
Spirometry (FEV1, FEV1/FVC) was performed using an EasyOn-PC spirometer and Easyware software (ndd Medizintechnik) AG, Zurich, Switzerland) according to American Thoracic Society and European Respiratory guidelines. Spirometry reference values were from Stanojevic.
Timepoint [5] 316830 0
6 years
Secondary outcome [6] 316831 0
Following baseline measures of spirometry (FEV1), Salbutamol (200 mcg) was administered to children using a Volumatic spacer (Glaxo Wellcome, Germany) and 15 minutes later spirometry was repeated. A positive response to bronchodilator was defined as >= 12% change from baseline FEV1.
Timepoint [6] 316831 0
6 years
Secondary outcome [7] 316832 0
Fractional exhaled nitric oxide (FEno) was measured using the chemiluminescence method method. Measurements were taken using a Niox MINO machine (Aerocrine AB, Solna, Sweden) and the six second exhalation mode to American Thoracic Society and European Society standards.
Timepoint [7] 316832 0
6 years
Secondary outcome [8] 316833 0
Faecal microbiota
Timepoint [8] 316833 0
4 and 6 years
Secondary outcome [9] 316834 0
The presence of S aureus in nasal and groin swabs
Timepoint [9] 316834 0
12 months, 4 and 6 years
Secondary outcome [10] 316835 0
Buccal DNA
Timepoint [10] 316835 0
Collected either at 4 or 6 years
Secondary outcome [11] 316836 0
Height and weight will be combined into a composite measure of body mass index (BMI) with children defined as underweight, normal, overweight or obese. Height will be measured with children standing upright on a stadiometer. Weight will be measured with children standing upright on calibrated digital scales.
Timepoint [11] 316836 0
At 4, 6 and 11 years, height and weight will be used as separate outcomes and in the defintion of BMI to describe children that are overweight or obese.
Secondary outcome [12] 316837 0
The Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV)
Timepoint [12] 316837 0
Age 11 years
Secondary outcome [13] 316838 0
Behavior Rating Inventory of Executive Function (BRIEF)
Timepoint [13] 316838 0
Age 11 years
Secondary outcome [14] 316839 0
The Centre of Epidemiological Studies Depression Scale for Children
Timepoint [14] 316839 0
Age 11 years
Secondary outcome [15] 316840 0
The Strengths and Difficulties questionnaire (SDQ)
Timepoint [15] 316840 0
Age 11 years
Secondary outcome [16] 316841 0
The Conners Continuous Performance Test 3rd Edition TM (Conners CPT 3 TM)
Timepoint [16] 316841 0
At age 11 years
Secondary outcome [17] 316842 0
Conners 3rd Edition TM (Conners 3 TM)
Timepoint [17] 316842 0
Age 11 years
Secondary outcome [18] 316843 0
Multidimensional Anxiety Scale for Children 2nd Ed (MASC 2)
Timepoint [18] 316843 0
Age 11 years
Secondary outcome [19] 316844 0
The CANTAB Executive Function Measures
Timepoint [19] 316844 0
Age 11 years
Secondary outcome [20] 316845 0
Head circumference using a tape measure at birth, 3, 12 and 24 months
Timepoint [20] 316845 0
Birth, 3, 12 and 24 months
Secondary outcome [21] 316846 0
Length measured at birth, 12 and 24 months using a measuring mat.
Timepoint [21] 316846 0
Birth, 12, 24 mth.
Secondary outcome [22] 316847 0
Weight measured at birth, 12 and 24 months using calibrated digital baby scales with the infant lying flat.
Timepoint [22] 316847 0
Birth, 12 and 24 months
Secondary outcome [23] 316848 0
Blood pressure using Dinamap automatic sphygmomanometer
Timepoint [23] 316848 0
11 years
Secondary outcome [24] 318893 0
Patient Orientated Eczema Measure (POEM) is a measure of eczema severity with a one week recall period to be completed by either the mother or the child.
Timepoint [24] 318893 0
At age 11 years

Eligibility
Key inclusion criteria
a) Pregnant women at least 37 weeks gestation
b) Pregnant women where they or their partner has a history of asthma, hay fever of eczema treated by a doctor.
Minimum age
No limit
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
a) Planning to move from study centres during study period
b) Birth weight lower than the 3rd percentile for gender and gestation
c) Infant admission to neonatal unit for at least 48 hours
d) Serious congenital abnormalities
e) Long-term probiotic use in mother
f) Mother intends to give probiotics to child if they develop eczema
g) Mother has taken less than 2 weeks study probiotics during pregnancy

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)
Allocation concealment was through central randomisation by computer at the Auckland University clinical trials pharmacy. Capsules were then placed in containers numbered with the appropriate study id.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Study ids were randomly assigned to study group by an independent clinical trials pharmacist at Auckland University using a computer generated list. At enrolment the participant was assigned the next study id on the list.
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
This study had two intervention groups and one control group. Participants in one intervention group took Lactobacillus rhamnosus HN001, and in the other intervention group took Bifidobacteria animalis subsp. lactis HN019.
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/01/2004
Actual
21/01/2004
Date of last participant enrolment
Anticipated
Actual
26/05/2005
Date of last data collection
Anticipated
Actual
24/11/2016
Sample size
Target
510
Accrual to date
Final
474
Recruitment outside Australia
Country [1] 615 0
New Zealand
State/province [1] 615 0

Funding & Sponsors
Funding source category [1] 2667 0
Government body
Name [1] 2667 0
Health Research Council New Zealand
Country [1] 2667 0
New Zealand
Funding source category [2] 2668 0
Commercial sector/Industry
Name [2] 2668 0
Fonterra New Zeland
Country [2] 2668 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
P O Box 7343,
Wellington South,
Newtown,
Wellington,
Country
New Zealand
Secondary sponsor category [1] 2411 0
University
Name [1] 2411 0
University of Auckland
Address [1] 2411 0
Private Bag 92019,
Auckland Mail Centre,
Auckland 1142,
Country [1] 2411 0
New Zealand
Other collaborator category [1] 64 0
Other Collaborative groups
Name [1] 64 0
University of Western Australia
Address [1] 64 0
Princess Margaret Hospital for Children,
GPO Box D 184, Perth,
WA 6001,
Country [1] 64 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 4587 0
Wellington Ethics Committee
Ethics committee address [1] 4587 0
Ministry of Health,
P O Box 5013,
Wellington,
Ethics committee country [1] 4587 0
New Zealand
Date submitted for ethics approval [1] 4587 0
Approval date [1] 4587 0
24/12/2002
Ethics approval number [1] 4587 0
WGT/01/08/00/095 AKX/02/00/280

Summary
Brief summary
Probiotics (found in fermented foods) when given to infants may exert a protective effect on the development of allergy by influencing the developing immune system. This study aims to determine whether dietary supplementation in infants with 2 different probiotics results in differences in atopy and eczema prevalence at age 2 years.
Trial website
Trial related presentations / publications
1. Kristin Wickens, Peter Black, Thorsten Stanley, Edwin Mitchell, Penny fitzharris, Gerald Tannock, Gordon Purdie, Julian Crane and the Probiotic Study Group. A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind randomized, placebo-controlled trial 2008;122:788-94
2. James Dekker, Kristin Wickens, Peter Black, Thorsten Stanley, Edwin Mitchell, Penny Fitzharris, Gerald Tannock, Gordon Purdie, Julian Crane. Safety aspects of probiotic bacterial strains Lactobacillus rhamnosus HN001 and Bifidobacteria animalis subsp lactis HN019 in human infants aged 0-2 years. International Dairy Journal 2009; 19149-54
3. Susan L. Prescott, Kristin Wickens, Lauren Westcott, Wiebke Jung, Helen Currie Peter N. Black, Thorsten V. Stanley, Edwin A. Mitchell, Penny Fitzharris, Rob Siebers, Lian Wu, Julian Crane and the Probiotic Study Group.
Supplementation with Lactobacillus rhamnosus or Bifidobacterium lactis probiotics in pregnancy increases cord blood IFN-y and breast milk TGF-B and IgA detection. Clin Exp Allergy 2008;38:1606-14
4. K Wickens, P Black, TV Stanley, E Mitchell, C Barthow, P Fitzharris, G Purdie, J Crane. A protective effect of Lactobacillus rhamnosus HN001 against eczema in the first 2 years of life persists to 4 years. Clin & Exp Allerg 2012;42:1071-9
5. Wickens K, Stanley TV, Mitchell E, Barthow C, Fitzharris P, Purdie G, Siebers R, Black PN, Crane J. Early supplementation with Lactobacillus rhamnosus HN001 reduces eczema prevalence to 6 years: does it also reduce atopic sensitization? Clin Exp Allergy 2013: doi:10.1111/cea.12154.
6. Morgan AR, Han DY, Wickens K, Barthow C, Mitchell E, Stanley TV, Dekker J, Crane J, and Ferguson LR Differential modification of genetic susceptibility to childhood eczema by two probiotics Clin Exp Allergy 2014;44:1255-65
7. Gareth Marlow, Dug Yeo Han, Kristin Wickens, Thorsten Stanley, Julian Crane, Edwin A. Mitchell, James Dekker, Christine Barthow, Penny Fitzharris, Lynnette R. Ferguson and Angharad R. Morgan. Differential effects of two probiotics on the risks of eczema and atopy associated with single nucleotide polymorphisms to toll-like receptors Paed Allergy Immunol 2015 In press
Public notes

Contacts
Principal investigator
Name 28082 0
Dr Kristin Wickens
Address 28082 0
Wellington School of Medicine and Health Sciences
Otago University
P O Box 7343
Wellington South
Wellington 6242
New Zealand
Country 28082 0
New Zealand
Phone 28082 0
+64 4 918 6780
Fax 28082 0
Email 28082 0
[email protected]
Contact person for public queries
Name 11239 0
Professor Julian Crane
Address 11239 0
Wellington Asthma Research Group,
Wellington School of Medicine and Health Sciences,
P O Box 7343,
Wellington South,
Wellington,
Country 11239 0
New Zealand
Phone 11239 0
0064 4 3855 999
Fax 11239 0
0064 4 389 5427
Email 11239 0
[email protected]
Contact person for scientific queries
Name 2167 0
Professor Julian Crane
Address 2167 0
Wellington Asthma Research Group,
Wellington School of Medicine and Health Sciences,
P O Box 7343,
Wellington South,
Wellington,
Country 2167 0
New Zealand
Phone 2167 0
0064 4 385 5999
Fax 2167 0
0064 4 389 5427
Email 2167 0
[email protected]

No information has been provided regarding IPD availability


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
EmbaseEffects of Lactobacillus rhamnosus HN001 in early life on the cumulative prevalence of allergic disease to 11 years.2018https://dx.doi.org/10.1111/pai.12982
EmbaseEczema-protective probiotic alters infant gut microbiome functional capacity but not composition: Sub-sample analysis from a RCT.2019https://dx.doi.org/10.3920/BM2017.0191
N.B. These documents automatically identified may not have been verified by the study sponsor.