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.

Eligibility Criteria:
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