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Trial registered on ANZCTR


Registration number
ACTRN12617001380381
Ethics application status
Approved
Date submitted
20/09/2017
Date registered
28/09/2017
Date last updated
16/04/2021
Date data sharing statement initially provided
6/11/2018
Date results information initially provided
16/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The PEBBLES study – Testing a strategy for preventing eczema and food allergy in high risk infants
Scientific title
THE PEBBLES STUDY: A randomised controlled trial to prevent eczema, food allergy and sensitisation using a skin barrier improvement strategy
Secondary ID [1] 292693 0
Nil known
Universal Trial Number (UTN)
U1111-1201-0431
Trial acronym
PEBBLES
Linked study record
ACTRN12609000727246: The PEBBLES Pilot Study
ACTRN12613000472774: The PEBBLES study: Prevention of Eczema By a Barrier Lipid Equilibrium Strategy

Health condition
Health condition(s) or problem(s) studied:
Eczema/Atopic Dermatitis 304447 0
Food Allergy 304448 0
Condition category
Condition code
Skin 303778 303778 0 0
Dermatological conditions
Inflammatory and Immune System 303779 303779 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Twice daily use of a ceramide dominant cream (EpiCeram) to infants skin. Ingredients in the formulation are Capric Acid, Cholesterol, Citric Acid, Conjugated Linoleic Acid, Dimethicone, Disodium EDTA, E. Cerifera (Candelilla)
Wax, Food Starch Modified Corn Syrup Solids, Glycerin, Glyceryl Stearate, Hydroxypropyl Bispalmitamide MEA
(Ceramide), Palmitic Acid, PEG-100 Stearate, Petrolatum, Phenoxyethanol, Potassium Hydroxide, Purified Water,
Sorbic Acid, Squalane, Xanthan Gum.
Parents will be instructed to apply EpiCeram™ to the full skin surface of their child twice per day. The prophylactic use of EpiCeram™ is the intervention that is being tested for its effect on infant skin barrier function. We will instruct parents to apply approximately 6 grams of EpiCeram™ per application at two regular times each day, including after bathing the infant, or at the time they would normally bathe their child. The PEBBLES study recruiter will demonstrate the application of the cream to parents during the baseline assessment. Duration of treatment is 6 months.
Mothers will be asked to bring all tubes of cream (both used and unused) with them to all follow-up assessments (when the child is approximately 6 weeks, and 6 months (26 weeks) of age), so that the study coordinator can weigh the remaining cream. This will allow for an estimate of the total amount of cream applied to the baby’s skin. We will also ask mothers how frequently cream was applied and how often applications were missed (Survey 4), and to complete a diary card documenting the days on which cream was applied (Diary Card – treatment group, Diary Card – no treatment group). Non-adherence will be defined as using the study cream on average for less than five days per week (once per day).
Intervention code [1] 298934 0
Treatment: Drugs
Intervention code [2] 299173 0
Prevention
Comparator / control treatment
The study staff will not provide any directions to parents in the control arm on how to manage their child's skin. No attempt will be made to alter or influence parents treatment of their child's skin in this arm of the study. This is defined as standard skin care. Duration of care is 6 months.
Control group
Active

Outcomes
Primary outcome [1] 303145 0
Presence of eczema as assessed using i) the UK working party criteria for eczema and/or ii) blinded investigator observed eczema.

Timepoint [1] 303145 0
12 months of age.
Primary outcome [2] 303449 0
Confirmed diagnosis of food allergy at 12 months (52 weeks). This diagnosis is derived from a combination of allergic sensitisation, reaction history and food challenge. A skin prick test to six common allergens will be performed (egg white, cows’ milk, peanut, dust mite, cat dander, and rye grass) along with a negative (saline) and a positive (histamine) control. Participants that are sensitised to certain foods (>=1mm wheal) during the skin prick testing will be given a challenge to determine if they are allergic to those foods. This will be conducted at the MCRI Allergy Clinic under the supervision of a Doctor specifically trained in oral food challenges.
Timepoint [2] 303449 0
12 months of age.
Secondary outcome [1] 338028 0
Skin barrier function - as assessed by Trans-epidermal water loss.
Timepoint [1] 338028 0
6 weeks and 12 months of age.
Secondary outcome [2] 338030 0
Eczema severity assessed using the EASI score.
Timepoint [2] 338030 0
12 months of age.
Secondary outcome [3] 338031 0
Parent report of a community doctor diagnosis of eczema.
Timepoint [3] 338031 0
12 months of age.
Secondary outcome [4] 338032 0
Skin prick test reactivity to any of six allergens; (egg white, cows’ milk, peanut, dust mite, cat dander, and rye grass). Both a negative (saline) and a positive (histamine) control will be used.
Timepoint [4] 338032 0
12 months of age.
Secondary outcome [5] 339132 0
To determine the level of parental compliance with a program to build infant skin barrier function as assessed by parental completion of weekly diary cards and weighing of the tubes of study cream at each visit
Timepoint [5] 339132 0
At 6 weeks and 6 months of age.
Secondary outcome [6] 339133 0
To confirm that a ceramide dominant emollient does not cause adverse effects in infants as assessed by the documentation of any untoward medical occurrence in a participant enrolled into this study.
Timepoint [6] 339133 0
From recruitment of infant until final study visit at 12 months of age.
Secondary outcome [7] 339134 0
To determine the level of compliance required to demonstrate an improvement in infant skin barrier function as assessed by the parental completion of weekly diary cards and weighing of the tubes of study cream at each visit.
Timepoint [7] 339134 0
6 weeks, 6 and 12 months of age.
Secondary outcome [8] 339135 0
skin microbial colonisation and skin lipid profile as assessed by tape stripping
Timepoint [8] 339135 0
At 6 weeks and 12 months of age.

Eligibility
Key inclusion criteria
Infants will be eligible for this study if their mother, father, or an older sibling has a self-reported history of at least one of the following conditions:
asthma,
eczema/atopic dermatitis,
hay fever/ allergic rhinitis
or food allergy.
Minimum age
No limit
Maximum age
3 Weeks
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Infants with any of the following will be excluded:
A parent who has a known hypersensitivity to any of the ingredients of EpiCeram™ will be excluded, as it would be difficult for these parents to apply EpiCeram™ to their infant, and there is likely to be an increased risk of the infant reacting to the cream.
Multiple births (twins, triplets etc.) will be excluded, due to the difficulty in randomising individual twins and because of the clustering effect of multiple children from the same family which would reduce the effective sample size of the study.
Who are born premature (<36 weeks) as the effect of the intervention may be different in premature infants.
Who have major birth or early life medical complications that require admission into a special care nursery, as it will be difficult for parents to comply with the study requirements.
Whose parents do not have sufficient English language skills to be able to answer questions.
Whose parents are not able to comply with all protocol required visits and procedures.

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)
Randomisation will be undertaken using a web-based random allocation list in blocks of variable length (4-12) set up within the trial database (REDCap). At all times, the allocation list will be concealed from the research team and the other study investigators, who manage participant recruitment.
The PEBBLES study recruiter will enter participant details into the randomisation database, and at the end of this process, will be given the participant study ID number, and the group of allocation. If the infant is allocated to the intervention group, the study recruiter will call each Pharmacy Department by telephone at the end of the baseline assessment to request that the study treatment be prepared for the participant. Randomisation will be stratified by recruiting centre and for number of immediate family members affected by allergic disease (1 vs 2+).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer generated random allocation list will be generated with variable blocks sizes. Randomisation will be stratified for the number of parents affected by allergic disease (1vs 2). Simple randomisation will be used, with equal numbers of children being allocated to the control and intervention groups.
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
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We will require 760 participants (380 in each group). With 380 infants per group, we will have (1) 86% power to demonstrate that the intervention causes an absolute risk reduction for eczema of 12% (from 40% to 28%, RR=0.7), and (2) 84% power to detect a 11% reduction in sensitisation (from 33% to 22%, RR=0.66), and 3) 80% power to detect a 7.5% reduction in food allergy at 12 months (from 15% to 7.5%, RR=0.5). The estimates of baseline risk of eczema and sensitisation come from our published clinical trial in a similar population, while the prevalence of food allergy comes from our observational study. These estimates allows for up to a 20% loss to follow-up and an alpha of 0.05. Our recent trials have achieved a higher rate of follow-up, making this a conservative estimate.
Secondary aim: The population prevalence of FLG null mutations is approximately 10%, so in this high risk population we expect it to be at least 15%. This will result in 45 infants per group (allowing for loss to follow-up) with one or more such mutations. We will have approximately 80% power to detect a relative risk of 0.40 (20% vs 50%) induced by the treatment for the outcome of eczema. for the control group to 19 g/cm2/hour in the intervention group (assuming a sd = 11 and an alpha level of 0.05).
The primary analysis will be the comparison of primary outcomes at six, and 12 months of age between participants in the standard skin care group and the intervention group. The primary analysis will be performed using the using the modified intention to treat (ITT) principle analysis. Regardless of the level of compliance with the study protocol or whether they discontinued use of the study treatment, they will be analysed in the group to which they were allocated. The modification of ITT will be that a complete case analysis will be performed. For our main dichotomous outcome measures (eczema, food allergy), the magnitude of any between-group differences will be quantified by calculating relative risk ratio, as well as absolute risk difference and number needed to treat, with 95% confidence intervals for the corresponding population estimates. Further analyses using multivariable log-binomial regression will be undertaken to explore the sensitivity of the effect estimates to imbalance between the groups at baseline on prognostic factors. Parental compliance to the intervention will be defined as 5 days per week (at least once per day), and a planned per-protocol analysis including only those infants in the intervention group who meet this level of treatment compliance, will be performed. . Both parental report of frequency of administration, and weight of cream used will be used as a potential predictor of risk of eczema. This will help determine if less frequent (or smaller quantity of) application of the study cream could be sufficient to reduce the risk of eczema.


Recruitment
Recruitment status
Active, not recruiting
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 in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 8833 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 8834 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [3] 8836 0
Frances Perry House - Parkville
Recruitment postcode(s) [1] 16970 0
3052 - Parkville
Recruitment postcode(s) [2] 16971 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 297335 0
Government body
Name [1] 297335 0
National Health and Medical Research Council
Address [1] 297335 0
GPO Box 1421
Canberra ACT 2601
Country [1] 297335 0
Australia
Funding source category [2] 297338 0
Commercial sector/Industry
Name [2] 297338 0
Primus Pharmaceuticals
Address [2] 297338 0
7373 N Scottsdale Rd, Scottsdale, AZ 85253, USA
Country [2] 297338 0
United States of America
Primary sponsor type
University
Name
University of Melbourne
Address
Parkville VIC 3010
Country
Australia
Secondary sponsor category [1] 296311 0
None
Name [1] 296311 0
Address [1] 296311 0
Country [1] 296311 0
Other collaborator category [1] 279676 0
Hospital
Name [1] 279676 0
Murdoch Children's Research Institute
Address [1] 279676 0
50 Flemington Road
Parkville,Victoria 3052.
Country [1] 279676 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298436 0
Royal Children's Hospital
Ethics committee address [1] 298436 0
50 Flemington Road
Parkville,Victoria 3052.
Ethics committee country [1] 298436 0
Australia
Date submitted for ethics approval [1] 298436 0
09/08/2017
Approval date [1] 298436 0
09/11/2017
Ethics approval number [1] 298436 0
37090
Ethics committee name [2] 301626 0
Mercy Health Human Research Ethics Committee (EC00230)
Ethics committee address [2] 301626 0
163 Studley Road Heidelberg, Vic, 3084
Ethics committee country [2] 301626 0
Australia
Date submitted for ethics approval [2] 301626 0
01/02/2018
Approval date [2] 301626 0
11/05/2018
Ethics approval number [2] 301626 0
2018-008

Summary
Brief summary
The primary objective of this study is to demonstrate that twice daily application of a ceramide dominant emollient reduces the risk of eczema and food allergy, when compared to standard skin management. Secondary objectives are to determine if twice daily application of a ceramide dominant emollient reduces the risk of infants developing allergic sensitisation (as measured by skin prick test); to determine if twice daily application of a ceramide dominant emollient improves infant skin barrier function; to determine the level of parental compliance with a program to build infant skin barrier function; to confirm that a ceramide dominant emollient does not cause adverse effects in infants; to determine the level of compliance required to demonstrate an improvement in infant skin barrier function and to determine if twice daily application of a ceramide dominant emollient influences infant skinmicrobial colonisation, or skin lipid profile.
This is a phase III, single blind (outcome assessor is blinded), randomised controlled multicentre trial of the effect of EpiCeram emollient for improving and maintaining skin barrier function and reducing incidence of eczema and food allergy in high risk infants.
A total of 760 participants with a first degree family history of allergic disease (asthma, eczema, allergic rhinitis or food allergy) will be recruited (380 each group) from maternity wards of seven hospitals.
Treatment will be from birth until six months, with a six week, six month and twelve month follow-up. An initial assessment will be performed at baseline which incorporates three surveys, a skin assessment, diary card (which is to be completed weekly and measures compliance), a breast milk sample, guthrie card and tape stripping. The six week assessment entails a skin assessment, survey, compliance check, breast milk sample, tape stripping and guthrie card, while the six month assessment entails a survey. Primary outcomes are assessed at the 12 month follow up where in addition to the aforementioned items, a saliva sample will also be taken and skin prick testing and food challenges will be performed when children have a positive SPT to one or more foods..
Trial website
https://mspgh.unimelb.edu.au/centres-institutes/centre-for-epidemiology-and-biostatistics/engage/pebbles
Trial related presentations / publications
Lowe AJ, et al. A randomized trial of a barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitization: the PEBBLES pilot study. BJD. 2017, Vol 178/1.
Lowe, A.J., et al., A phase I study of daily treatment with a ceramide-dominant triple lipid mixture commencing in neonates. BMC Dermatol, 2012. 12: p. 3.
Lowe, A.J., et al., A randomised trial of a barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitisation: The PEBBLES Pilot Study. Br J Dermatol, 2017 (accepted 15/6/2017).
Public notes

Contacts
Principal investigator
Name 77082 0
A/Prof Adrian Lowe
Address 77082 0
Allergy and Lung Health Unit
Centre for Epidemiology and Biostatistics
Melbourne School of Population and Global Health
University of Melbourne VIC 3010
Level 3, 207 Bouverie Street
Country 77082 0
Australia
Phone 77082 0
+61 3 8344 0878
Fax 77082 0
+61 3 9349 5815
Email 77082 0
lowea@unimelb.edu.au
Contact person for public queries
Name 77083 0
Ms Shaie O'Brien
Address 77083 0
Allergy and Lung Health Unit
Centre for Epidemiology and Biostatistics
Melbourne School of Population and Global Health
University of Melbourne VIC 3010
Level 3, 207 Bouverie Street
Country 77083 0
Australia
Phone 77083 0
+61 3 8344 0643
Fax 77083 0
+61 3 9349 5815
Email 77083 0
sdobrien@unimelb.edu.au
Contact person for scientific queries
Name 77084 0
A/Prof Adrian Lowe
Address 77084 0
Allergy and Lung Health Unit
Centre for Epidemiology and Biostatistics
Melbourne School of Population and Global Health
University of Melbourne VIC 3010
Level 3, 207 Bouverie Street
Country 77084 0
Australia
Phone 77084 0
+61 3 8344 0878
Fax 77084 0
+61 3 9349 5815
Email 77084 0
lowea@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Intervention group, outcome data, and potential predictors of outcome.
When will data be available (start and end dates)?
from 1/10/2021 onwards (no end date)
Available to whom?
Academic researchers
Available for what types of analyses?
Grouped analyses or individual participant meta-analyses.
How or where can data be obtained?
contacting Adrian Lowe (lowea@unimelb.edu.au)
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary