Efficacy and Safety of Viaskin Milk in Children With IgE-Mediated Cow's Milk Allergy

The objectives of this study are to evaluate the safety and efficacy of Viaskin Milk after 12 months of epicutaneous immunotherapy (EPIT) treatment, for desensitizing IgE-mediated cow's milk allergic children and to assess the long-term safety and therapeutic benefit with Viaskin Milk.

This is a multi-center, double-blind, placebo-controlled, randomized trial to study the safety and efficacy of Viaskin Milk applied epicutaneously every day to subjects from 2 to 17 years of age with IgE-mediated cow's milk allergy (CMA). Subjects will receive blinded treatment for 1 year at one of the 3 doses of Viaskin Milk: 150µg, 300µg, 500µg or placebo. After the first year, all subjects were to switch to the highest dose of Viaskin Milk, 500µg, and continue treatment in an open-label manner for up to a maximum of 3 additional years. Following results of the 12-month blinded period, all eligible subjects who wish to continue participation in the study will switch from Viaskin Milk 500µg to Viaskin Milk 300µg for 24 months of treatment.

Eligible subjects with confirmed IgE-mediated CMA will perform a first Double-Blind Placebo-Controlled Food Challenge (DBPCFC) at screening with escalating doses of cow's milk proteins. Subjects showing a positive DBPCFC at screening, defined as the appearance of objective signs or symptoms to an eliciting dose of cow's milk proteins ≤300 mg (approximately ≤9.4mL of cow's milk) will be randomized in the study to receive a 12 month treatment (blinded treatment period), at which time a second DBPCFC will be performed to evaluate the primary efficacy endpoint of the study.

Approximately 194 subjects will be randomized in this study. The total duration of participation in the study will differ for each individual subject and could be up to approximately 6 years.

Eligibility Criteria:
Eligibility criteria for study enrollment:

Inclusion Criteria:

* Signed Informed Consent Form (ICF) by parent(s)/guardian(s) of subjects and informed assent form (IAF) for subjects ≥7 years, or as per local or country specific guidelines or regulations.
* Male or female subjects 2 to 17 years old at Visit 1.
* Documented medical history or physician-confirmed diagnosis of IgE-mediated CMA with systemic symptoms related to ingestion of milk or dairy products.
* Subjects currently following a strict cow's milk-free diet, with no consumption of dairy or baked milk products.
* Cow's milk-specific IgE level at screening ≥10 kU/L
* Positive Skin Prick Test (SPT) to cow's milk with a largest wheal diameter ≥6 mm.
* Positive DBPCFC at screening with an eliciting dose ≤300 mg cow's milk proteins (approximately ≤9.4 mL of cow's milk).
* Negative urine pregnancy test for female subjects of childbearing potential. Female subjects of childbearing potential must agree and commit to use effective medical methods of contraception for the entire duration of their participation in the study. Sexual abstinence will be accepted as an effective method of contraception for girls below 15 years of age.
* Ability to perform spirometry procedures in accordance with the American Thoracic Society guidelines (2005) for subjects ≥6 years old. Ability to perform peak expiratory flow (PEF) measurements for subjects ≥5 years old. Subjects \<8 years of age who have documented inability to adequately perform spirometry can perform only the PEF evaluation. Subjects \<5 years of age may be enrolled if they had no clinical features of moderate or severe persistent asthma severity (as defined by the 2007 National Heart, Lung, and Blood Institute \[NHLBI\] Guidelines) within 1 year before Visit 1.
* Subjects and/or parents/guardians willing to comply with all study requirements during participation in the study.

Exclusion Criteria:

* History of severe anaphylaxis to cow's milk resulting in hypotension, hypoxia or neurological compromise (collapse, loss of consciousness or incontinence) or requiring mechanical ventilation.
* Pregnancy or lactation.
* Spirometry forced expiratory volume in 1 second (FEV1) \<80% of the predicted value at Visit 1 for subjects ≥6 years and able to perform the spirometry, or PEF \<80% of predicted value at Visit 1 for subjects performing only the PEF measurements.
* Any clinical features of moderate or severe persistent asthma severity (as defined by the 2007 NHLBI guidelines) and high daily doses of inhaled corticosteroids.
* Known allergy to the Viaskin patch materials or excipients, or to any of the components of the food challenge formulas other than the cow's milk proteins.
* Allergy or known history of reaction to Tegaderm® medical dressing with no possibility to use an alternative adhesive dressing authorized by the sponsor in replacement.
* Subjects having objective symptoms to the placebo formula leading to stopping the challenge during the screening DBPCFC.
* Severe reaction during the screening DBPCFC defined as need for intubation, and/or hypotension persisting after epinephrine administration, and/or the need for \>2 doses of epinephrine.
* Symptomatic allergy to pollens with symptoms during the pollen season that might interfere with the symptoms observed during the DBPCFC, if the DBPCFC is performed during the pollen season. Screening of such subjects should be made out of the pollen season.
* Inability to discontinue short-acting antihistamines for 3 days or long-acting antihistamines for 5 to 7 days (depending on the half-life) before the DBPCFC.
* Use of systemic long-acting corticosteroids within 12 weeks before Visit 1 and/or use of systemic short-acting corticosteroids within 4 weeks before Visit 1 or use of systemic long-acting or short-acting corticosteroids during screening (unless used to treat symptoms triggered by the DBPCFC or triggered by accidental allergen consumption; in the latter case DBPCFC must then be scheduled after a minimum of 7 wash-out days).
* Subjects with asthma conditions meeting 1 or several criteria below:

  * Uncontrolled persistent asthma (as defined by the 2007 NHLBI guidelines) or subject being treated with a combination therapy of medium or high daily dose of inhaled corticosteroid with a long acting inhaled β2-agonist. Intermittent asthmatic subjects who require intermittent use of inhaled corticosteroids for rescue are permitted.
  * At least 2 systemic corticosteroid courses for asthma within 1 year before Visit 1 or 1 oral corticosteroid course for asthma within 3 months before Visit 1, or during screening (unless used to treat symptoms triggered by the DBPCFC).
  * Prior intubation/mechanical ventilation due to asthma within 2 years before Visit 1, or during screening.
* Upper respiratory infection or gastroenteritis within 7 days of DBPCFC (DBPCFC must then be rescheduled at least 7 days after resolution of these conditions).
* Any history of milk immunotherapy (eg, oral immunotherapy, sublingual immunotherapy or specific oral tolerance induction).
* Prior history of any other food allergen immunotherapy (eg, oral immunotherapy, sublingual immunotherapy or specific oral tolerance induction) within 5 years before Visit 1.
* Subjects currently under aeroallergen immunotherapy and unwilling or unable to discontinue at the time of Visit 1. Aeroallergen Immunotherapy must be discontinued at the time of Visit 1.
* Use of any anti-IgE drug (eg, omalizumab), any immunomodulatory therapy, or any biological agent therapy (eg, anti-tumor necrosis factor drugs) within 1 year before Visit 1, or during screening.
* Generalized dermatologic diseases (eg, severe atopic dermatitis, uncontrolled generalized eczema, icthyosis vulgaris) with no intact zones to apply the Viaskin patch, or urticarial and mast cells disorders such as chronic idiopathic urticaria.
* Subject and/or subject's parents/guardians with obvious excessive anxiety and unlikely to cope with the conditions of a food challenge.
* Past or current disease, including but not limited to active eosinophilic gastrointestinal disorders, autoimmune disorders, immunodeficiency, malignancy, uncontrolled disease (hypertension, diabetes, psychiatric disorder, cardiac disease), or other disorders (eg, liver, gastrointestinal, kidney, cardiovascular, pulmonary disease or blood disorder) which in the opinion of the Investigator or the sponsor may affect the subject's participation in the study or place the subject at increased risk.
* Subjects and/or parents/guardians unable to use the epinephrine auto-injector properly in spite of being adequately trained.
* Contraindicated condition for the use of epinephrine.
* Use of any investigational drug or device, or participation in another interventional clinical study within 3 months before Visit 1.
* Subjects receiving beta-blockers or Angiotensin converting-enzyme (ACE) inhibitors.
* Subjects unable to follow the protocol requirements.