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Trial registered on ANZCTR


Registration number
ACTRN12613000472774
Ethics application status
Approved
Date submitted
23/04/2013
Date registered
26/04/2013
Date last updated
24/09/2019
Date data sharing statement initially provided
24/09/2019
Date results information initially provided
24/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The PEBBLES study: Prevention of Eczema By a Barrier Lipid Equilibrium Strategy
Scientific title
Does twice daily application of a ceramide dominant cream (EpiCeram) for the first six months of life reduce the incidence of eczema by six months of age, when compared to standard skin care, in infants who have a family history of allergic disease
Secondary ID [1] 282389 0
ACTR12609000727246: The PEBBLES Pilot Study
Universal Trial Number (UTN)
U1111-1142-2705
Trial acronym
PEBBLES
Linked study record

Health condition
Health condition(s) or problem(s) studied:
eczema 288970 0
Condition category
Condition code
Skin 289308 289308 0 0
Dermatological conditions

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. Approximatly six grams will be applied twice per day. Duration of treatment is 6 months.
Intervention code [1] 287021 0
Treatment: Drugs
Intervention code [2] 287031 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] 289417 0
Presence of eczema as assessed using the UK working party criteria for eczema
Timepoint [1] 289417 0
6 weeks and 6 months post randomisation
Primary outcome [2] 289418 0
Transepidermal water loss (TEWL) as assessed using Vapometer on the infants forearm and forehead
Timepoint [2] 289418 0
6 weeks and 6 months post randomisation
Secondary outcome [1] 302427 0
Presence of eczema, as assessed using the UK working party criteria for eczema, six months post cessation of study treatment
Timepoint [1] 302427 0
12 months post randomisation
Secondary outcome [2] 302428 0
Probable eczema, as defined by diagnosis of eczema by medical practitioner that was not verified by the study investigators.
Timepoint [2] 302428 0
During treatment period (0 to 6 months), and for six months (7 to 12 months of age) post cessation of treatment
Secondary outcome [3] 302429 0
Eczema severity as measured by SCORing Atopic Dermatitis (SCORAD)
Timepoint [3] 302429 0
6 weeks, 6 months & 12 months of age
Secondary outcome [4] 302430 0
Skin prick test reactivity to six common food (cows' milk, peanut and hens egg) and areo-allergens (house dust mite, rye grass and cat dander), defined as a wheal of 3mm or greater than the negative saline control.
Timepoint [4] 302430 0
6 and 12 months post randomisation
Secondary outcome [5] 302431 0
Biomechanical properties of the skin (pH, hydration, oiliness) assessed using a Skin-pH-Meter (PH905), Coneometer (CM 825), and Sebumeter (SM 815) from Courage + Khazaka electronic
Timepoint [5] 302431 0
6 weeks, 6 and 12 months post randomisation

Eligibility
Key inclusion criteria
Either mother and/or father has a self reported history of:
- asthma and/or
- eczema/atopic dermatitis and/or
- hayfever/allergic rhinitis and/or
- food allergy
Minimum age
1 Days
Maximum age
3 Weeks
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- A parent who has a known hypersensitivity to any of the ingredients of EpiCeram.
- Multiple births (twins, triplets etc.)
- Premature infants (<36 weeks)
- Infants with major birth or early life medical complications that require admission into a special care nursery.
- Infants 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)
The random allocation list will be held by the Royal Children's Hospital (RCH) Pharmacy Department. Pharmacy staff will be independent from the participant recruitment or testing. The allocation list will be concealed from the study co-ordinator and other study investigators who will manage participant recruitment.
The PEBBLES study co-ordinator will call the RCH Pharmacy Department by telephone at the end of the one week-baseline assessment to determine the group of allocation. The study co-ordinator will provide the child's name and this will be recorded on the allocation list. The infant will be allocated to the next study number and assigned to the group corresponding to that unique study identification number
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 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
With 40 participants per group, we should have sufficient numbers to be able to demonstrate that EpiCeram (Trademark) causes an important reduction in risk of eczema and an increase in the infants’ skin barrier function. Based on our recent experience with a similar study (Probiotics in the Prevention of Eczema Prevention of Eczema – PEPS) that used a comparable selection criteria and outcome assessment, approximately 35% of infants in the control group will show evidence of eczema at three or six months of age. Given that this is a reasonably intensive treatment, and the substantial impact that EpiCeram has as a treatment for eczema, we expect a large reduction in the symptoms of eczema in the intervention group.

Due to slower than anticipated recruitment rate, the sample size estimate was re-estimated. The revised estimate is based on having 80% power to detect a very large difference in eczema at six months (35% in controls, 5% in intervention group). The revised sample size is 34 children per group, or a 80 total to allow for approximately a 15% drop out rate.

If we have 40 infants per group, we will have over 80% power to detect a difference in TEWL of 26 g/cm2/hour for the control group to 19 g/cm2/hour in the intervention group (assuming a sd = 11 and an alpha level of 0.05).

Data will be analysed using the intention to treat principle; that is that regardless of the level of compliance with the study protocol, or if they discontinued use of the EpiCeram treatment, they will be analysed in the group to which they were allocated.

If there are clear differences between the groups on baseline risk factors that are associated with risk of allergic disease (gender, exposure to cigarette smoke, parental level of education) multiple logistic or linear regression models will be used to adjust for these baseline imbalances. Baseline TEWL (at 1 week of age) will also be considered as a potential confounder of the effect of the intervention.

A per-protocol analysis will be performed to determine if a certain amount of compliance (at least an average of three days application, or 36 grams, of cream per week) is required for the treatment to be effective. Both parental report of frequency of administration, and weight of cream used will be used as a potential predictor of risk of eczema values. 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
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 in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 941 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 942 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 943 0
Frances Perry House - Parkville
Recruitment postcode(s) [1] 6797 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 287162 0
Charities/Societies/Foundations
Name [1] 287162 0
The Financial Markets Foundation for Children
Address [1] 287162 0
GPO Box 3655
Sydney
NSW 2001
Country [1] 287162 0
Australia
Funding source category [2] 287164 0
Charities/Societies/Foundations
Name [2] 287164 0
The Asthma Foundation of Victoria
Address [2] 287164 0
491 – 495 King Street
West Melbourne
Vic 3003
Country [2] 287164 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Murdoch Childrens Research Institute
Address
Murdoch Childrens Research Institute
Royal Children's Hospital
Flemington Road Parkville Victoria 3052 Australia
Country
Australia
Secondary sponsor category [1] 285931 0
None
Name [1] 285931 0
Address [1] 285931 0
Country [1] 285931 0
Other collaborator category [1] 277368 0
Commercial sector/Industry
Name [1] 277368 0
PuraCap Pharmaceutical LLX
Address [1] 277368 0
1001 Durham Avenue
South Plainfield
New Jersey
07080
Country [1] 277368 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289159 0
Royal Children's Hospital Human Research Ethics Committee
Ethics committee address [1] 289159 0
Research Development & Ethics
The Royal Children's Hospital Melbourne
50 Flemington Road
Parkville 3052
Victoria
Ethics committee country [1] 289159 0
Australia
Date submitted for ethics approval [1] 289159 0
Approval date [1] 289159 0
30/11/2012
Ethics approval number [1] 289159 0
29132
Ethics committee name [2] 289161 0
Royal Women's Hospital Human Research Ethics Committee
Ethics committee address [2] 289161 0
Research and Ethics Secretariat
The Royal Women's Hospital
Locked Bag 300
Cnr Grattan St & Flemington Rd
Parkville 3052
Victoria
Ethics committee country [2] 289161 0
Australia
Date submitted for ethics approval [2] 289161 0
Approval date [2] 289161 0
25/02/2013
Ethics approval number [2] 289161 0
10/05

Summary
Brief summary
Asthma affects approximately 20% of children, is a common cause of hospital admissions, and we do not know how to stop children developing it. Infantile eczema is also common, affecting about a third of children. Infants with eczema often later develop asthma. It is hypothesised sensitisation to allergens can occur via damaged skin associated with eczema, which then increases the risk of asthma.
If this hypothesis is correct, it may be possible to prevent asthma by improving the skin barrier function in infants. There is evidence that a ceramide based emollient (which contains the major components of skin) can improve skin barrier function, while current treatments for eczema do not.
This study is aims to determine if twice daily application of a ceramide dominant emollient can improve infant skin barrier function and prevent the development of eczema in high risk children.
Trial website
No trial website
Trial related presentations / publications
Published pilot study results:
Lowe AJ, Tang ML, Dharmage SC, Varigos G, Forster D, Gurrin LC, Robertson CF, Abramson MJ, Allen KJ, Su J: A phase I study of daily treatment with a ceramide-dominant triple lipid mixture commencing in neonates. BMC Dermatol 2012, 12: 3.

Final trial publication:
Lowe AJ, Su JC, Allen KJ, Abramson MJ, Cranswick N, Robertson CF, 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 2018;178(1):e19-e21.
Public notes

Contacts
Principal investigator
Name 39518 0
Dr Adrian Lowe
Address 39518 0
Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne,Level 3, 207 Bouverie Street VIC 3010
Country 39518 0
Australia
Phone 39518 0
+61 3 8344 0878
Fax 39518 0
Email 39518 0
lowea@unimelb.edu.au
Contact person for public queries
Name 39519 0
Dr Adrian Lowe
Address 39519 0
Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne,Level 3, 207 Bouverie Street VIC 3010
Country 39519 0
Australia
Phone 39519 0
+61 3 8344 0878
Fax 39519 0
Email 39519 0
lowea@unimelb.edu.au
Contact person for scientific queries
Name 39520 0
Dr Adrian Lowe
Address 39520 0
Centre for Molecular, Environmental, Genetic, Analytic (MEGA) Epidemiology
School of Population and Global Health
The University of Melbourne
Level 3, 207 Bouverie Street
Carlton VIC 3010
Country 39520 0
Australia
Phone 39520 0
+61 3 8344 0878
Fax 39520 0
Email 39520 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?
Eczema and food senstisation outcomes
When will data be available (start and end dates)?
From 23/9/2019. No end date determined
Available to whom?
Research groups approved by the study investigators
Available for what types of analyses?
pooled and de-identified analyses
How or where can data be obtained?
By contacting A/Prof Adrian Lowe
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
Analytic code
How or where can supporting documents be obtained?
Type [1] 4974 0
Study protocol
Citation [1] 4974 0
Link [1] 4974 0
Email [1] 4974 0
lowea@unimelb.edu.au
Other [1] 4974 0
Attachment [1] 4974 0
Type [2] 4975 0
Informed consent form
Citation [2] 4975 0
Link [2] 4975 0
Email [2] 4975 0
Other [2] 4975 0
By contacting A/Prof Adrian Lowe
Attachment [2] 4975 0
Type [3] 4976 0
Ethical approval
Citation [3] 4976 0
Link [3] 4976 0
Email [3] 4976 0
lowea@unimelb.edu.au
Other [3] 4976 0
Attachment [3] 4976 0
Type [4] 4977 0
Analytic code
Citation [4] 4977 0
Link [4] 4977 0
Email [4] 4977 0
lowea@unimelb.edu.au
Other [4] 4977 0
Attachment [4] 4977 0
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 4973 0
Lowe AJ, Su JC, Allen KJ, MJ Abramson MJ, Cranswick N, CF Robertson CF, Forster D, Varigos G, Hamilton S, Kennedy R, Axelrad C, Tang MLK, Dharmage SC. A randomised trial of a barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitisation: The PEBBLES Pilot Study. British Journal of Dermatology. 2018: 178; e19-21.
Attachments [1] 4973 0
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary
In this pilot study (80 infants), we assessed if the application of a specific cream (EpiCeram™) to the skin of new-born infant’s twice-daily for six months, would help build up skin barrier function and reduce the risk that these children would develop eczema and allergic sensitisation to foods. Our results revealed a trend towards a reduced risk of eczema and food sensitisation in infants from the ‘cream’ group at 12 months of age, particularly if it was used from within the first two weeks of life, and applied regularly. This was the first time that possible beneficial effects of this type of treatment beyond the treatment period have been demonstrated