Preventing Atopic Dermatitis and ALLergies in Children
Preventing Atopic Dermatitis and ALLergies in Children
The primary objective is of the PreventADALL study is to test if primary prevention of
 allergic diseases is possible by simple and low cost strategies, and secondary to asses the
 impact of xenobiotic exposure and microbiota in and on the body and the environment on
 allergic disease development.

 The secondary objective is an exploratory focus to investigate early life risk factors for
 development of non-communicable diseases, including asthma and allergic diseases as well as
 for diseases that may share common risk factors, including cardiovascular disease, obesity
 and diabetes.

 Design: A multi-national population-based prospective birth cohort with a factorial designed
 randomized controlled intervention trial of two clinical interventions; skin care 0-9 months
 and early food introduction by 3-4 months, thereafter observation only.

 Recruitment in three cities (Oslo, Ostfold and Stockholm) of approximately 2500 mother-child
 pairs is done in two steps; first pregnant women are recruited and enrolled at the 18-weeks
 ultrasound investigation (n=approximately 2700) and thereafter their new-born babies are
 included.

 Randomization into four groups is done by the postal code or "township" to ensure all four
 intervention-groups within each "township".

 Visits for biological and environmental sampling, observations and investigations will be at
 the relevant pediatric departments (at 3-6-12-24-36 months of age) and through childhood into
 adulthood thereafter, provided sufficient funding.
The PreventADALL study is a long term prospective birth cohort study, with an intervention
 aspect designed as a randomized clinical trial (RCT), and an exploratory aspect, enrolling
 mother-child pairs by including pregnant women, allowing for intrauterine investigations of
 the baby and maternal factors during pregnancy, and thereafter including their new-born
 babies for long-term follow-up investigations.

 With the knowledge that allergic diseases often manifest in early infancy, interventions will
 be carried out as early as possible to investigate if allergic diseases can be prevented. Two
 interventions, early and systematic introduction to common foods, and early skin care are
 carried out within the first four months and the first nine months of life, respectively.

 Inclusion/Exclusion criteria:

 Ante-natal inclusion, step 1: All mothers to-be at 18 weeks ultrasound investigation with
 sufficient language skills (Norwegian or Swedish), gestational age: at least 16-22 weeks.
 Exclusion: Plans to move further than reasonable travel distance from any of the
 participating hospitals within the first year of the offspring's life.

 Inclusion of the child, step 2: Live-born babies of gestational age 35.0 weeks or more
 (including multiple pregnancies), maternal/parental willingness to participate in the study
 Exclusion criteria child: 1) severe neonatal cardiac, pulmonary, neurological, dermatological
 disease or other disease that may influence the outcomes 2), plans to move further than
 reasonable travel distance away from any of the participating hospitals within the first nine
 months of life.

 3) Non-willingness to participate 4) More than two fetuses

 Overall design:

 A multi-national population-based prospective birth cohort with a factorial designed
 randomized controlled intervention trial of two clinical interventions; skin care 0-9 months
 and early food introduction by 3-4 months continuing to at least 6 moths and preferentially
 continuing thereafter. Observation only after nine months of age. Recruitment is done in two
 steps; first pregnant women at the 18-weeks ultrasound investigation and thereafter their
 new-born babies.

 Randomisation into four groups is done by the postal code or "township" to ensure all four
 intervention-groups within each "township".

 Electronic questionnaires will be completed by the mother at 18 and 34 weeks gestation, as
 well as for the baby at 3-6-9-12-18-24-30-36 months and annually thereafter. Also, an
 electronic diary will be completed each week from 2-26 weeks of age, to register weekly
 interventions, as well as symptoms of allergic diseases and food intake.

 Visits for biological and environmental sampling, observations and investigations will be at
 the relevant pediatric departments (at 3-6-12-24-36 months of age) and annually thereafter.
 It is a hope that the study can be maintained well into adulthood.

 The study will be run in accordance with Good Clinical Practice (GCP).

 Investigations:

 Clinical investigations and biological sampling focuses on: General development, clinical
 assessments of health or disease, as well as diagnosing allergic disease and later also other
 non-communicable diseases (NCD)s.

 These include:

 -  Fetal growth and respiratory development

 -  Somatic growth and status (anthropometric data)

 -  Blood pressure

 -  Skin, respiratory, gastrointestinal and other relevant organs

 -  Skin barrier (trans epidermal water loss (TEWL))

 -  Lung function and -development

 -  Microbiota/diversity (in and on the body and the environment)

 -  Viral infections

 -  Immune-deviation/tolerance development

 -  Specific allergen antibodies (IgE/IgG)

 -  Xenobiotics and interactions between exposures (microbiota/xenobiotics)

 -  Genetics/epi-genetics

 Outcome measures:

 Primary outcomes from birth to assessment times, first at 12 months of age for AD and at 36
 months for food allergy to intervention allergens:

 1. Atopic dermatitis (AD), Food allergy to any intervention allergen

 2. Allergic sensitization (yes/no as well as quantitative, by skin prick test and s-IgE)
 Secondary outcomes: annually (ie 12, 24, 36, months and further follow-up investigations
 through childhood into adulthood): asthma (bronchial obstruction in year 1-2) and/or
 food allergy to any other allergen and/or anaphylaxis and/or allergic rhinitis Later
 outcomes for the exploratory part of the study will be defined in terms of obesity,
 cardiovascular diseases and diabetes.

 For assessments of food allergy, first determined at three years of age, we will harmonize
 study protocols with similar studies.

 Interventions:

 Skin intervention (IS): Skin care is performed from week 2 through 8 months of age,
 supervised by study personnel prior to leaving the hospital.

 Food intervention (IF): Major food allergens (cow's milk, peanut, wheat, egg) are introduced
 no later than 4.0 months of age as tastes, not interfering with nutrition.

 Safety assessment: An external surveying committee to assess adverse events and main outcomes
 will be established prior to study start, to assess safety and potential needs for
 re-assessing interventions. The safety committee is offered free access to any data they
 need, at their discretion.

 Statistical approaches: Stratum randomization, logistic regression analyses (primary
 outcomes), mixed models (continuous outcomes particularly of allergic sensitization by
 quantification) will be applied. An external surveillance committee will monitor the safety
 aspects with availability to reports whenever, and whatever clinical or other criteria they
 deem appropriate. Their assessment will have the potential to stop the trial in case of large
 differences in the groups. However, due to the short time span of observation before the
 interventions are completed, it is unlikely that intervention differences may be observed
 prior to completion.

 Power analysis lack underlying data and is therefore based upon the prevalence Environment
 and Childhood Asthma study (ECA study) of AD at two years of age for skin barrier
 intervention only. The prevalence (%) of (ever) allergic disease in the ECA study were at 2,
 10 and 16 years of age: Asthma: 8 (recurrent bronchial obstruction), 20 and 26.4%, Atopic
 eczema: 23.2, 33.2 and 34.8%, Allergic rhinitis (10 and 16 years): 19 and 32.1%, Allergic
 sensitization (10/16 years): 37.4 and 52.6%, respectively. Data on food allergy is lacking.

 The investigators' pilot study suggested a prevalence reduction in AD from 16 to four % at
 6-months of age in children with dry skin subjected to skin care from 2 weeks. Thus, an
 estimated reduction from 23.2 % to 18.2 % (five per cent points) in a general population
 would be highly clinically relevant, worthwhile and feasible and require 1030 children in
 each skin care versus observation group to attain an 80 % power at 5% significance level. A
 reduction to 19.2 % (four per cent points) requires 1638 children per group.

 Recent publications demonstrated approximately 30 % reduction in atopic dermatitis at 32
 weeks of age after daily use of skin care and 50% risk reduction at 6 months of age in 124
 high risk children, respectively suggesting that approx. 1000 babies in each group would be
 sufficient to detect significant and relevant reductions in AD in a factorially 2x2 designed
 study. With many sub-studies we aim for 2400-2500 mother-child pairs.

 In line with emerging study results (2015) the power-estimates will be repeated with
 potential modification of population size requirement until the target population is
 recruited.

 Study Phases:

 The first phase of the PreventADALL study; to establish the birth cohort study, collect
 information and biological samples, closely assess the children in the first 3 years of life,
 assess the impact of the two interventions and the impact of microbiota and xenobiotic
 exposure on early allergic disease presentation.

 This phase will also create the foundation for a long-term follow-up study with careful
 assessments of potential risk or protective factors for allergic as well as other NCDs at the
 start of life. The PreventADALL study will lead to improved knowledge of the potential effect
 of primary prevention and of management of allergic diseases in early life as well as
 improving knowledge of risk factors for NCDs later in life.
The study enrolls Mother-child pairs in two steps; first mother, thereafter her new-born
 baby.

 Inclusion Criteria:

 1. Ante-natal inclusion, step 1: All mothers to-be at 18 weeks ultrasound investigation
 with sufficient language skills (Norwegian or Swedish), gestational age: at least 16-22
 weeks.

 1. Exclusion: Plans to move further than reasonable travel distance from any of the
 participating hospitals within the first year of the offspring's life.

 1. Inclusion of the child, step 2: Live-born babies of gestational age 35.0 weeks or more
 (including multiple pregnancies), maternal/parental willingness to participate in the study

 Exclusion Criteria:

 Exclusion criteria child: 1) severe neonatal cardiac, pulmonary, neurologic, dermatologic
 disease or other disease that may influence the outcomes 2), plans to move further than
 reasonable travel distance away from any of the participating hospitals within the first
 nine months of life.

 3) Non-willingness to participate, 4) More than two foetuses