A double-blind, placebo-controlled, randomized phase III trial to assess the safety and efficacy of Viaskin Peanut in peanut-allergic young children 1-3 years of age (EPITOPE study)

See section: 1.1 "Background in the protocol"

To assess the safety and efficacy of DBV712 in initiating desensitisation of
peanut in children aged 1 to 3 years with peanut allergy, after 12 months of
treatment with Epicutaneous Immunotherapy EPIT).

In previous clinical studies in peanut allergic children 4 to 11 years old,
Viaskin Peanut 250 µg has been demonstrated as a safe and effective treatment
for inducing desensitization to peanut.
However, Viaskin Peanut has never been assessed in younger children from 1 to 3
years old. The present study is designed to assess in this population the
safety of 2 doses of Viaskin® Peanut in the first part of the study (Part A)
and then to demonstrate the efficacy and safety of the selected dose in the
second part (Part B).
Part A has already been completed abroad. Only Part B of the study will run in
The Netherlands.

This is a 12-month, phase III, double-blind, placebo-controlled, randomized
trial to assess the safety and efficacy of Viaskin Peanut in peanut-allergic
children 1 to 3 years of age.
The trial will be conducted in between 20-40 sites with Investigators and
staffs trained and experienced in the diagnosis and the management of peanut
allergy and anaphylaxis, and capable to perform Double-Blind Placebo-Controlled
Food Challenge (DBPCFC) in toddlers and young children.
Peanut allergic children meeting the following key inclusion criteria will be
selected: physician-diagnosed peanut allergy or high suspicion of peanut
allergy as assessed by the physician (child presenting signs, symptoms and a
medical and/or a family history putting him/her at high risk of having a peanut
allergy and/or history of presence of peanut-specific immunoglobulin E [IgE]
and/or positive Skin Prick Test [SPT]); subject currently following a strict
peanut-free diet; presence of peanut-specific IgE > 0.7 KU/L; positive SPT to
peanut extract with the largest wheal diameter >= 6 mm; positive DBPCFC to
peanut with an Eliciting Dose (ED) <= 300 mg of peanut protein.

Study part B:
The second part of the study will aim at assessing the safety and efficacy of
the selected dose after a 12-month treatment versus placebo. This part will be
initiated after the choice of the highest safe dose upon the DSMB meeting. As
from protocol v6.0, the selected highest safe dose for part B upon DSMB
recommendation is 250 µg. Additional subjects will be recruited in the active
selected dose arm and in the placebo arm to reach the targeted total number of
subjects.
In accordance with the calculated sample size for this study, a total of 350
additional subjects will be randomized in the second part or Part B of the
study. These subjects will be randomized with a 2:1 ratio in favor of the
active arm, i.e. 233 subjects in the active arm and 117 subjects in the placebo
arm.
An interim analysis to evidence the treatment activity on the immune system of
children 1 to 3 years old is planned when the first 50 subjects have reached 6
months of active treatment with Viaskin Peanut 250 µg. This analysis will be
specifically conducted on the peanut- specific IgG4 measurements. The relative
change from baseline of the peanut-specific IgG4


levels in the Viaskin Peanut 250 µg treatment group at Month 6 will be
numerically compared to the relative change from baseline of the
peanut-specific IgG4 levels in the placebo group at Month 6. The median
relative change in IgG4 of the selected active Viaskin Peanut treatment group
is expected to be greater than the median relative change in IgG4 of the
placebo treatment group.
In the situation where the median relative change from baseline of the
peanut-specific IgG4 in the Viaskin Peanut 250 µg group is equal to or lower
than the median relative change from baseline of the peanut-specific IgG4 in
the placebo group, the premature stop of the study will be considered for lack
of evidence of therapeutic benefit. This unblinded data review will be
conducted by the DSMB who will be responsible of issuing the recommendation to
the Sponsor.
The overall maximum study duration for each subject is approximately 60 weeks
(6-week screening period, 12-month (or 52 weeks) treatment period and a 2-week
follow-up period). During the screening period, subjects will perform a first
screening visit and an entry DBPCFC to peanut to confirm their allergy and
their entry peanut ED. The starting dose of the challenge will be set to 1 mg
peanut protein up to the highest dose of 300 mg peanut protein. Subjects who
react at or below the dose of 300 mg peanut protein will be eligible and will
be randomized in the study.
A post-treatment DBPCFC will be performed at Month 12, starting at the dose of
1 mg peanut protein and proceeding up to the highest dose of 2,000 mg peanut
protein. The primary efficacy endpoint of this phase III study is the
difference between the percentage of treatment responders in the selected
DBV712 group (250 µg) compared to the placebo group at Month 12, determined on
the peanut protein ED during the food challenge.
Other efficacy assessments at months 3, 6 and 12, include immunological changes
in peanut- specific IgE and IgG4 and SPTs.
Key assessments of global safety will be performed at each study visit
including skin observation of the patch areas of application, vital signs,
physical examinations, clinical laboratory assessments. Atopic dermatitis will
also be assessed at baseline and at months 3, 6 and 12 using the SCORing Atopic
Dermatitis (SCORAD).
Between the visits, the severity of 3 pre-specified local skin reactions will
be assessed on a daily basis by the parents/guardians in a diary, for the first
6 months of treatment for part A subjects, and during the whole treatment
duration for part B subjects. Any other Adverse Events (AEs) (including any
local skin reactions other than the 3 pre-specified ones at any time of the
study, and any pre-specified local skin reactions occurring after the first 6
months of treatment for part A subjects), and any concomitant medications will
be also reported in the diary by the parents/guardians and this will be
reviewed by the site medical staff at each subject visit.
At screening and at Month 12, the subjects* parents/guardians will complete
quality of life questionnaires (FAQLQ/FAIM Food Allergy Quality of Life
Questionnaire / Food Allergy Independent Measure-parent form / EQ-5D-5L [part B
only]) to assess the impact of 12-month treatment with Viaskin Peanut on their
quality of life.
In addition, the adhesion of the Viaskin patch to the skin and the occlusion of
the condensation chamber will be assessed daily by the subjects*
parents/guardians in a diary during the whole duration of treatment. This
assessment will be conducted in part B only. The trained site staff will also
assess the patch adhesion of all subjects at each subject visit.
After completion of this 12-month blinded study, eligible subjects, including
the subjects in the placebo group and in the non-selected active treatment
group (100 µg), will be offered the opportunity to participate in an extension
study to receive 24 additional months of treatment with Viaskin Peanut 250 µg.
Subjects satisfying the inclusion and exclusion criteria of the extension study
will be invited to participate in the extension study

Viaskin Peanut 250 µg for 12 months. This is done by comparing it with a
placebo for the entire 12 months to demonstrate that the effect is really due
to the medication and is independent of interpretation from participants or
study doctors. To make this comparison between Viaskin Peanut 250 µg and
Viaskin placebo.

There is no approved treatment other than strict avoidance for peanut food
allergy. If the subject is not enrolled, there is no treatment proposed.
Therefore, he/she will receive the standard-of-care treatment, that is to say,
*strict avoidance*.

Possible risks and discomfort
As with all research studies, the study patches and study procedures may
involve unknown risks. Any medication can have temporary and permanent side
effects and can cause unforeseen adverse reactions. The study patches may fail
to control/reduce your child*s peanut allergy. The procedures for peanut
allergy in this study - either routine in medical practice or experimental for
study purposes - do not have special risks. In some cases, examinations, Skin
Prick Tests, blood samples or the Viaskin patches administration, especially at
the start, may cause some discomfort.

Known Side effects of Viaskin Peanut
The study medication may cause some side effects. These could include:
• Skin reactions (for example application site pruritus (itching), erythema
(redness), macule (small circumscribed changes in the color of skin that are
neither raised (elevated) nor depressed), papule (small solid rounded bumps
rising from the skin), irritation and application site eczema
(redness,swelling, crusting, and thickening of the skin) are the most
frequently reported adverse reactions, occurring in more than 10% of patients;
other skin reaction at application site: swelling, urticaria and darkened
coloring of the skin are commonly reported adverse reaction, occurring in less
than 10% of patients (>=1% and <10%). The less frequently reported skin
application site adverse reaction (Uncommon: >=0.1% and <1%) are application
site excoriation, application site bleeding, application site infection and
application site pain. Most of local adverse reactions associated with patch
application were mild to moderate in severity.
• Severe skin reactions (pruritus, erythema, swelling) at the patch application
site or possibly extending beyond the patch application area may also occur.
• Reactions distant from the site of patch application such as symptoms that
may suggest a local transitory allergic reaction due to presence of peanut
allergen trace amount on fingers following contact with the patch and further
touching of the eyes have been reported. These reactions include conjunctivitis
allergic, eye swelling and redness of eyes . These distant symptoms occur in
less than 10% ofpatients (>=1% and <10%);
• Anaphylaxis, which can potentially be life-threatening, include distant
symptoms, as well such as hives, itchy throat, lip swelling, rash,difficult
breathing, coughing, sneezing, vomiting, abdominal pain and, in the most severe
cases, may lead to a general feeling of uneasiness. Anaphylaxis has been
reported in less than 10% of patients (>=1% and <10%) during testing of study
treatment in children with more than one allergy. In completed studies,
systemic allergic reactions reported as anaphylacitic reactions were reported
in slightly numerically more patients treated with Viaskin® Peanut than with
placebo (5.1% vs 2.8%). All anaphylactic reaction reported as related to
Viaskin® Peanut were mild to moderate, characterized mainly by skin reactions
as well as subjective respiratory symptoms with no cardiovascular nor
respiratory compromise. In Viaskin Peanut treated patients, these anaphylactic
reactions tended to occur early during the treatment (within 2 months from
treatment initiation), led to brief treatment interruption and did not recur
while continuing treatment. The majority resolved either without epinephrine or
following one injectable epinephrine administered at home.
If your child experienced any other symptoms you can talk with your study
doctor. Please ask the study doctor if you have any questions about the known
and possible side effects of Viaskin Peanut. See Appendix D on the ICF for more
information