Gastrointestinal-release capsule intended for use in a method to desensitize and / or induce tolerance in a subject allergic to peanuts.

Abstract

Gastrointestinal release capsule intended for use in a method for desensitizing and / or making tolerant a subject allergic to peanuts, or alternatively for diagnosing a peanut allergy in a subject, said capsule comprising a shell and a core, said core comprising a peanut composition including peanut, at least one oil, at least one first powdered excipient, and optionally at least one second prebiotic excipient.

Description

Title of the invention: CASTROINTESTINAL RELEASE CAPSULE FOR USE IN A METHOD FOR DESENSITIZING AND / OR INDUCING TOLERANCE IN A SUBJECT ALLERGIC TO PEANUTS Technical field of the invention

[0001] The field of the invention is that of pharmaceutical composition and medical indications. More specifically, the invention relates to a gastrointestinal release capsule comprising a core and a shell, said core comprising a peanut composition, said capsule being intended to be used in an oral immunotherapy method for desensitizing a subject allergic to peanut, and / or for inducing tolerance to peanut in a subject allergic to this allergen. Said capsule is also intended to diagnose a peanut allergy in a subject. Technical background

[0002] Peanut allergy affects 1% to 2% of the pediatric population. It ranks first among food allergies in children over 3 years of age. Unlike chicken egg or cow's milk allergy, peanut allergy disappears in only 20% of cases (Rance et al, Clin. Exp. Allergy, 2005, 35:167-172). It is potentially serious: the ingestion of small quantities of peanut can in fact lead to serious or even lethal reactions. These reactions are the result of a mechanism mediated by immunoglobulin E (IgE), both for the initial reaction - which leads to the diagnosis of peanut allergy - and for subsequent and unpredictable reactions during accidental or hidden ingestions.

[0003] These allergic reactions occurring after ingestion of the allergen include respiratory (spasmodic cough, dyspnea, asthma attack), cutaneous (urticaria, chemosis, angioedema affecting the skin or the mucous membranes of the upper airways responsible for laryngeal dyspnea), digestive (abdominal pain, nausea, vomiting, diarrhea) or general manifestations, ranging from simple malaise to acute anaphylaxis with or without cardiovascular collapse generating shock. These severe symptoms are particularly related to the allergenic fraction ara h2 of peanut, but also to other peanut storage allergens such as ara hl and ara h3. It may also involve involvement of the upper airways (rhinitis, conjunctivitis, or oral syndrome with pruritus, erythema or edema reaching the oral cavity, even the pharynx) or upper digestive tract including eosinophilic esophagitis. Disgust towards peanuts is one of the classic signs of the disease. These signs are often associated and stages of severity have been described in the literature (Lieberman P, Nicklas RA, Oppenheimer J et al, The diagnosis and management of anaphylaxis: an updated practice parameter, J. Allergy Clin. Immunol. 2010;126:477-80). Children allergic to peanuts are therefore permanently exposed to the risk of anaphylactic reaction, which is regularly updated in the medical literature (Food allergy and Anaphylaxis guidelines: European Academy of Allergy and Clinical Immunology 2014).

[0004] The diagnosis of peanut allergy does not pose a problem in the face of a clinical history suggestive of a reaction after ingestion, in a patient sensitized by prior contact with peanut. The positivity of a skin test and a serum specific IgE assay to peanut testify to the patient's sensitivity to peanut. In case of doubt about the responsibility of peanut, the practice of an oral challenge test (OPT) is necessary to support the relationship between the allergen and the reaction it provokes. Thus the OPT is considered the "gold standard" for making the definitive diagnosis of peanut allergy, especially if it is carried out in a double-blind and placebo-controlled (DACP) fashion. It is also used to determine the reactogenic threshold to peanut and thus allow the adaptation of avoidance measures. Its practice involves specific preventive measures.It must be carried out in a department accustomed to its implementation (precise protocol, anticipated therapeutic measures) and capable of dealing with a super-acute reaction (resuscitation department nearby).

[0005] To overcome the nocebo effect, the use of the double-blind technique (patient and doctor blind) is recommended. The specific taste and smell of peanuts in their native form, however, make this practice difficult, particularly considering the practice of mixing the peanut composition with the food bolus. For clarification, the nocebo effect is the negative counterpart of the placebo effect. It is psychological in nature. More precisely, it appears when the patient develops harmful side effects even when consuming an inert substance. The development of these harmful side effects comes from the fact that the patient is convinced that the substance presented to them is harmful or that it will have harmful effects on them. In the case of peanuts, patients would be quick to develop allergies if they think they are allergic to peanuts, or at the very least to trigger an allergic reaction at much lower thresholds.

[0006] Until recent years, the therapeutic management of peanut allergy was limited to the strict dietary avoidance of peanuts. The observation of the higher frequency of serious reactions after accidental ingestion of peanuts in patients following a strict avoidance compared to that of children following a relative avoidance, has led to the practice in recent years of peanut tolerance induction protocols. However, an evaluation according to the Cochrane method has not been able to fully validate the concept, despite the results of several studies, in the absence of placebo control.

[0007] Immunotherapy methods aim to reduce the risk of a severe or even fatal reaction after accidental peanut ingestion and to improve the quality of life of patients suffering from this disease. The most widespread methods consist of the oral administration of peanut. They include an ingesta increment phase which aims at desensitization to the allergen (which requires the patient to continue to ingest small amounts of allergen to be protected), then a tolerance phase which protects the patient while he no longer ingests the allergen on a daily basis. As reported in numerous scientific publications, these oral tolerance inductions are conventionally carried out by mixing the peanut composition or equivalent with the food bolus. Indeed, it is commonly recognized that it is preferred, even essential, to expose the immune cells of the oral cavity and the esophagus to the peanut composition..

[0008] Furthermore, work is underway either with low doses applied to the oral mucosa sublingually, or in the form of larger doses ingested in the food bolus. In the current state of the literature, immunotherapy is not validated as a treatment technique for peanut allergy, for reasons relating to the acceptability of the treatment and patient compliance, and especially to the side effects of these oral immunotherapy techniques, in particular digestive side effects, including eosinophilic esophagitis, and anaphylactic reactions. Other methods based on epicutaneous application in the form of patches containing peanut have recently been developed.However, transdermal penetration of peanut allergen is less than that of oral immunotherapy and may vary depending on the functional quality of the skin (filaggrin deficiency demonstrated in atopic subjects, age, sex, race, etc.). After accidental ingestion, the doses that penetrate the body are often high: the effectiveness of transcutaneous desensitization in this case may therefore be doubted.

[0009] There is therefore a need to propose a simple, effective and safe means of desensitizing patients to peanuts. Objectives of the invention

[0010] The invention aims in particular to overcome these drawbacks of the prior art, in particular in terms of acceptability, efficacy and safety by reducing side effects.

[0011] More specifically, an objective of the invention is to provide, in at least one embodiment, a composition making it possible to desensitize and / or induce tolerance in subjects allergic to peanuts.

[0012] Another objective of the invention is to provide, in at least one embodiment, a composition making it possible to diagnose an allergy in a subject.

[0013] Another objective of the invention is to propose, in at least one embodiment, a composition making it possible to desensitize a subject allergic to peanuts in a comprehensive and definitive manner,

[0014] Another objective of the invention is to provide, in at least one embodiment, a composition intended to be used in a method for desensitizing and / or inducing tolerance in a subject allergic to peanuts, while effectively masking the taste, color and smell, thereby eliminating food disgust towards this allergen,

[0015] Another objective of the invention is to provide, in at least one embodiment, a composition intended to be used in a method for desensitizing and / or inducing tolerance in a subject allergic to peanuts, by reducing the side effects, in particular the risk of eosinophilic esophagitis and anaphylactic reaction.

[0016] Another objective of the invention is to provide, in at least one embodiment, a composition intended to be used in a method for desensitizing and / or inducing tolerance in a subject allergic to peanuts, while minimizing the occurrence of the nocebo effect.

[0017] Another objective of the invention is to provide, in at least one embodiment, a composition intended to be used in a method for desensitizing and / or inducing tolerance in a peanut-allergic subject aged 1 to 18 years. Summary of the invention

[0018] These objectives, as well as others which will appear subsequently, are achieved using an orally ingested capsule with gastrointestinal release, intended to be used in a method for desensitizing a subject allergic to peanuts and / or for inducing tolerance to peanuts in a subject allergic to this allergen, said capsule comprising a shell and a core, said core comprising a composition comprising peanut, at least one oil, at least one first powdered excipient, and optionally at least one second prebiotic excipient.

[0019] By "capsule" is meant a galenic form such as a hard or soft shell capsule or gelatin capsule, containing in its core a fixed quantity of peanut composition as well as a fixed quantity of excipients. The peanut composition is therefore isolated within the capsule, and is only made available after opening the capsule and / or breaking the shell. The capsules according to the invention are therefore distinguished from forms ingested in isolation or within the food bolus in the form of uncoated tablets, powders and liquid suspensions, in that the active ingredient (namely peanut presently) is not immediately available,

[0020] By "gastrointestinal release" is meant a capsule in which the capsule opening and / or the shell rupture occurs in the stomach and / or the small intestine. In other words, the integrity of the capsule is preserved during ingestion by the mouth and its passage via the esophagus. The capsule opening and / or the shell rupture occurs under the mechanical and physiological action of the stomach and / or the small intestine.

[0021] The mass percentage is calculated by the following formula: Mass percentage of a compound A (%) = (mass of A / total mass of the composition^ 100.

[0022] Thus, the invention is based on a completely new and original approach to orally administering peanuts while masking the characteristic odor, color and flavor of peanuts and minimizing the risk of allergic reaction or anaphylactic shock.

[0023] In particular, the capsule according to the invention is intended to be used in a method for desensitizing and / or making tolerant (inducing tolerance in) an allergic subject, while avoiding contact with the buccal, pharyngeal and esophageal mucous membranes, which are rich in immune cells and antigen-presenting cells in particular.

[0024] Antigen-presenting cells are cells of the immune system that present on their surface an antigenic fragment of the foreign molecule or organism, in this case the allergen. These cells can be monocytes, macrophages, B lymphocytes or dendritic cells. Schematically, this presentation of the antigen by immune cells allows a specific activation of the T lymphocytes which will recognize the epitope of the foreign molecule or organism in order to then be able to eliminate it.

[0025] The inventors therefore propose to bypass the oral cavity, the pharynx and the esophagus, and their reactive immune system to avoid the occurrence of an allergic reaction in the patient with each attempt at desensitization, which would in fact put an end to the therapeutic approach. Indeed, patients allergic to peanuts trigger more or less violent reactions in the event of contact. The unpredictability of these reactions and their intensity means that special precautions must be taken during a peanut immunotherapy protocol. In addition, the occurrence of a repeated or severe allergic reaction means that the desensitization protocol must be stopped. Avoiding an excessively violent allergic reaction is therefore crucial for the continuation and success of a peanut allergy and / or desensitization diagnostic procedure. In addition to these acute ingestion reactions, the shunt described above will reduce the risk of chronic allergy manifestations occurring, particularly at the local level of eosinophilic esophagitis. Note that this approach goes against many currently practiced approaches, which consist of mixing the peanut composition with the food bolus.

[0026] Furthermore, the mucosa of the small intestine is equipped with numerous specialized antigen-presenting cells, in particular mononuclear phagocytes of the macrophage type or dendritic cells. Intestinal dendritic cells thus constitute a set of heterogeneous subpopulations differentially expressing a certain number of phenotypic markers, including CD 103, CD11b, CD172a / SIRPa and CX3CRL. These subpopulations have different functional characteristics, in particular some of which would be fundamental in the establishment of oral tolerance to food antigens, in particular the migratory dendritic cells CD103+CD11b and to a lesser extent CD1034' CD11b+.Indeed, in homeostatic conditions, after migration into the mesenteric lymph nodes, these cells would have the capacity to produce retinoic acid thanks to an enzyme, RALDH2 (retinaldehyde dehydrogenase 2), as well as TGF-P and would express FIDO (indoleamine 2,3-dioxygenase). All of these elements would allow the conversion of naive T lymphocytes into peripheral regulatory T CD4+CD25+FoxP3 and their homing in the intestinal mucosa. These lymphocytes would then themselves be involved in the inhibition of Th2 and IgE responses specific to food antigens, and in the promotion of IgG4 responses. Dendritic cells could also promote the functioning of other regulatory T lymphocytes, of the Th3 type for example, as well as that of ILC (Innate Lymphoid cells) or regulatory B lymphocytes.A disruption in the functioning of dendritic cells can thus break the delicate balance of immunity vs. tolerance, generating the appearance of a Th2 type response and hypersensitivity to food allergens. The capsule according to the invention makes it possible to release the peanut in the small intestine and to bring these intestinal dendritic cells into contact with the antigen contained in the peanut composition. Thus, by targeting these intestinal dendritic cells (without the intervention of the presenting cells of the oropharynx), our “gastrointestinal release” immunotherapy acts directly on the cells actually supporting in vivo the induction of oral tolerance and makes it possible to optimize our immunotherapy protocol. Note that the contact between the intestinal dendritic cells and the allergens can take place in three preferential ways, 1) by direct contact thanks to the emission. cytoplasmic extensions by CX3CR1+ and CDHb+ dendritic cells of the Lamina proplia passing between the epithelial cells and capturing food allergens directly in the intestinal lumen; 2) by indirect contact following transcytosis of allergens through M cells located above Peyer's patches; 3) by indirect contact via intestinal epithelial cells capable of internalizing allergens at their apical pole, then secreting a tolerogenic cytokine environment at their basal pole in contact with dendritic cells, as well as exosomes carrying allergenic peptides.

[0027] Consequently, the stimulation of antigen-presenting cells in the small intestine is an interesting way to stimulate the patient's immune system while limiting the risks of allergic reaction. By avoiding contact with the oral, pharyngeal and esophageal mucosa, the composition according to the invention makes it possible, on the one hand, to make desensitization possible, and on the other hand, to reduce the precautions taken during desensitization tests or ingestion of the treatment.

[0028] Masking the characteristic taste, color and smell of peanuts also makes it possible to considerably reduce, if not eliminate, the nocebo effect. Indeed, it is notable that patients suffering from peanut allergy have a food aversion which constitutes a characteristic symptom of the disease. By consciously and visibly ingesting peanuts, the deleterious effect of which they know, they are likely to develop symptoms in every way identical to those of an allergic reaction. According to the invention, the capsule also makes it possible to best respect the principle of the double-blind test.

[0029] If necessary, as illustrated herein, the peanut may be pre-conditioned. For example, the peanut may be conditioned in the form of a paste, for example by adding an oil. The peanut paste will then constitute the raw material of the peanut composition.

[0030] The presence of a first powdery excipient is useful in that it makes it possible to obtain a peanut composition in powdery (powder) form, independently of the raw material used, such as peanut paste. This form facilitates the preparation and packaging of the peanut composition.

[0031] The presence of a second prebiotic excipient makes it possible to strengthen the commensal flora and contribute to strengthening the immunity of the subject treated.

[0032] The formulation of the peanut composition with these first and second excipients also makes it possible to modify the absorption of the peanut by the intestinal mucosa.

[0033] The capsule thus optimized makes it possible to maintain a presentation of the allergen in an intact form and thus to meet the objective of peanut immunotherapy.

[0034] The capsule according to the invention preferably comprises a composition of roasted peanuts, very preferably a composition of roasted and non-defatted peanuts.

[0035] The capsule according to the invention preferably comprises between 10 mg and 1000 mg, very preferably between 10 mg and 750 mg, still very preferably between 10 mg and 500 mg of peanut.

[0036] Said composition according to the invention may comprise between 5% and 70% of peanut, relative to the total weight of the composition. In addition, said composition may comprise between 15% and 55% of the first powdered excipient, relative to the total weight of the composition. Similarly, said composition may comprise between 10% and 75% of the second prebiotic excipient, if present, relative to the total weight of the composition.

[0037] The capsule can take different sizes. The size of the capsule can be adapted to its mass, while respecting the concept of pharmaceutical blindness. Thus, with regard to the active ingredients, excipients and other compounds, their respective proportions lung! be adjusted so that the appropriate dose of active ingredients is ingested by the subject to be treated, depending on the stage in progress.

[0038] Advantageously, the peanut composition comprises between 10% and 40%, preferably between 10% and 30%, very preferably between 15% and 25%, of allergenic proteins relative to the total weight of said composition. Indeed, the inventors have demonstrated that it is preferable, in order to avoid allergic reactions during the immunotherapy protocol, and in order to ensure effective desensitization, to use peanuts having a limited proportion of allergenic proteins, i.e. less than 40%, instead of peanuts having a high proportion of allergenic proteins.

[0039] As a corollary, said peanut composition comprises between 10% and 15% of the total proteins for the allergenic fraction Ara hl, between 2% and 10% of the total proteins for the allergenic fraction Ara h2 and between 10% and 20% of the total proteins for the allergenic fraction Ara h3; preferably approximately 12% of the total proteins for the allergenic fraction Ara hl, approximately 6% of the total proteins for the allergenic fraction Ara h2 and approximately 15% of the total proteins for the allergenic fraction Ara h3, by weight of the protein fraction of said composition. This particular composition of allergens, present in limited proportions, makes it possible to bring together the most frequent allergenic fractions among the great diversity of peanut varieties. Thus, the capsule according to the invention has an exhaustive and universal character for desensitization to peanut allergy.It is indeed interesting that a patient / subject can be desensitized to different allergenic fractions simultaneously, so that he can resume a normal life without worrying about the . variety of peanut used in a dish or having potentially contaminated the food product.

[0040] Said capsule preferably comprises an oil being sunflower oil. Allergy to sunflower oil is exceptional and does not expose to the risk of severe reaction. It is in fact not rare for patients allergic to peanuts to have other food sensitizations or allergies, and in particular to walnut, hazelnut or even rapeseed oil. Said composition may comprise between 0.5% and 5% of said oil, relative to the total weight of said composition.

[0041] Said capsule comprises a first powdered excipient being preferably tricalcium phosphate, very preferably a first powdered excipient chosen from beta tricalcium phosphate, alpha tricalcium phosphate, and their mixture; alternatively beta tricalcium phosphate or alpha tricalcium phosphate. The formulation of the peanut composition with tricalcium phosphate is advantageous, in comparison with other powdered excipients. Indeed, tricalcium phosphate is a potential adjuvant of immunity. This function therefore contributes to the desensitization of the subject treated,

[0042] Said capsule may further comprise a second prebiotic excipient being preferably lactose, very preferably lactose monohydrate. The formulation of the peanut composition with a second prebiotic excipient, in particular lactose, is advantageous in that said second prebiotic excipient contributes to improving the quality of the digestive commensal flora, which is essential in that it contributes greatly to the “education” of the immune system, and in that it is an essential factor in limiting the occurrence of allergic phenomena (on a population scale).

[0043] Said capsule according to the invention comprises between 20 mg and 315 mg of the first powdered excipient and / or between 0 mg and 100 mg of the second prebiotic excipient.

[0044] The shell of said capsule is preferably opaque, which makes it possible to prevent the patient and / or the practitioner from distinguishing the capsule containing the peanut composition from a placebo, for example. In this respect, the capsule according to the invention may also comprise an opacifier and / or colorants in its shell, to the extent of their inertness from an allergenic point of view.

[0045] The capsule shell may comprise a body and a head, the head being fixed to the body to close the capsule. In particular, the closed capsule may have a length of between 5 mm and 30 mm. The head of the shell may have a length of between 5 mm and 15 mm and a diameter of between 4.5 mm and 10 mm. The body of the shell may have a length of between 5 mm and 25 mm and a diameter of between 4.5 mm and 10 mm.

[0046] The capsule as defined above can be used to determine the reaction threshold of a peanut allergy. This threshold is determined in vivo by carrying out a provocation test. This justifies special preventive measures and a trained team as well as the presence of a resuscitation service nearby. The occurrence of an objective clinical reaction, even isolated, defines the threshold of reactivity (Table 4), (Rancé F., Deschildre A, Vilîard-Truc F, Gomez SA, Paty E, Santos C, Couderc L, Fauquert JL, De Blic J, Bidat E, Dupont C, Eigenmann P, Lack G, Scheinmann P, SFAIC and SP2A workgroup on OFC in children. Oral food challenge in children: an expert review. Position paper of the Section of Pediatrics of the French Society of Allergology and Clinical Immunology (SFAIC) and of the Pediatric Society of Pulmunology and Allergology (SP2A). Eur Ann Allergy Clin Immunol 2009;41;2:35-49.).

[0047] The diagnosis of peanut allergy should preferably be based on the practice of a double-blind oral provocation test (OPT) during which peanut or its allergens are administered to the patient. The characteristic odor and flavor of peanut make compliance with the double-blind test or diagnosis difficult. Furthermore, the possibility that a reaction may occur or be intensified by knowledge of the presence of the allergen can never be excluded. The capsule, by concealing the appearance, odor, color and flavor of its contents, makes it possible to avoid all these drawbacks. In addition, the presence of at least a first powdered excipient and optionally at least a second excipient makes it possible to improve its intestinal absorption. This is particularly interesting when it comes to accurately determining the threshold value of reactivity.

[0048] The invention relates in particular to the capsule as defined above for its use in a method for desensitizing and / or making tolerant (inducing tolerance in) a subject allergic to peanuts. The desensitization approach can also be designated by the expressions “specific immunotherapy” or “allergy vaccine therapy”. Desensitization consists of gradually reaccustoming the body to an allergen, by means of administering increasing doses of a composition comprising the allergen, until the effective dose is obtained. The desensitized patient then exhibits much more moderate allergic reactions in the presence of the allergen(s) in question. In the case of patients allergic to peanuts, desensitization allows them to consume foods potentially in contact with peanuts, or even foods containing them,

[0049] The subject to be desensitized is preferably aged between 1 and 18 years. Children and adolescents are particularly exposed to accidental ingestion of peanuts. For example, children or adolescents may be exposed to peanuts by eating at home. canteen, by sharing treats with their school friends or by themselves because they are unaware of the potential presence of peanuts or their traces in food products. The desensitization approach is therefore of particular interest to children and adolescents. Alternatively, the subject can be aged 18 or over.

[0050] Advantageously, the capsule according to the invention is provided and administered orally (ingested) in an unopened form and not mixed with the food bolus. Maintaining the integrity of the capsule during ingestion is essential at present in that it avoids bringing the immune cells present in the oral cavity, the pharynx and the esophagus into contact with the peanut. Thus, the peanut is only brought into contact with the immune cells of the stomach and the small intestine. Although many protocols require the capsules to be opened and / or the shells to be broken before ingestion, for mixing with the food bolus, the inventors have demonstrated that "bypassing" the immune system of the oral cavity, pharynx and esophagus, and specifically targeting the immune system of the stomach and small intestine, provides an effective desensitization method, while minimizing the risk of allergic reactions.

[0051] The immunotherapy method according to the invention consists of a phase of induction of a tolerogenic response of the immune system and / or desensitization, followed by a maintenance phase,

[0052] The desensitization phase may consist of the daily administration by at least one capsule of an increasing average dose of peanut from 10 mg to 2 g for 20 to 28 weeks, preferably for 24 weeks. The average dose of peanut is preferably increased up to a maximum factor of 2 in stages every 10 to 18 days, preferably every 14 days. The increasing average doses of peanut may be, for example: 10 mg / day, 20 mg / day, 40 mg / day, 80 mg / day, 160 mg / day, 300 mg / day, 500 mg / day, 750 mg / day, 1000 mg / day, 1250 mg / day, 1500 mg / day, and 2000 mg / day.

[0053] The maintenance phase may consist of the administration of an average daily dose of peanut of the order of 2g, preferably an average daily dose of peanut of between 2g and 5g. The maintenance phase is implemented with subjects aged 1 to 18 years, alternatively subjects of 18 years or older, tolerating a cumulative dose of peanut greater than 2g.

[0054] In another aspect, the present invention also relates to a gastrointestinal release capsule, as defined herein, for oral use in a method for diagnosing peanut allergy in a subject. Brief description of the figures

[0055] Other characteristics and advantages of the invention will appear more clearly on reading the following description of a preferred embodiment, given as a simple illustrative and non-limiting example, and the appended figures showing a synopsis of the progress of the clinical study protocol. - [Fig. 1] - [Fig. 1] represents a first diagram schematizing the progress of the study, and the method used; [Fig.2] - [Fig.2] represents another diagram outlining the progress of the study and the method used. Detailed description of the invention

[0056] The general principle of the invention is based on the formulation of capsules comprising a peanut paste which can be used on the one hand for the reliable and precise diagnosis of a peanut allergy and the allergy trigger threshold, and on the other hand for the desensitization of peanut allergy. The formulation in the form of capsules therefore makes it possible to avoid, or at least to greatly reduce, the nocebo effect which can distort diagnostic tests for a peanut allergy. It also makes it possible to know precisely and simply the dose of peanut administered to the patient. Finally, it facilitates the patient's desensitization protocol, in particular by avoiding any contact with the oral mucosa rich in immune cells.

[0057] Examples of capsule compositions according to the invention

[0058] The peanut paste used as raw material is composed of 95.7% peanuts, 4.3% sunflower oil and at least one excipient, namely tricalcium phosphate (powdery excipient), and optionally lactose (prebiotic excipient). The peanut paste is obtained by mixing peanut with said oil, in order to obtain a raw material. This peanut paste is then mixed with excipients, in order to obtain a peanut composition according to the invention. Thus, the peanut paste is incorporated in powder form into capsules of different sizes.

[0059] These capsule sizes correspond to very specific standards. The shell of each capsule is composed of a head and a body, the body being filled with peanut paste before the head closes the body.

[0060] The capsules according to the invention can take all sizes from size 000 (the largest) to size 4 (smallest),

[0061] [Table 1]

[0062] Detail of the capsule size standard 000 00 0 1 2 4 Capsule length closed (mm) 26.1 23.3 21.7 19.4 18.0 15.9 14.3 Body length (mm) 22.2 20.2 18.4 16.6 15.3 13.6 12.2 Head length (mm) 12.9 11.7 10.7 9.8 8.9 8.1 7.2 Body diameter (mm) 9.5 8.2 7.3 6.6 6.1 5.6 5.0 Head diameter (mm) 9.9 8.5 7.6 6.9 6.3 5.8 5.3

[0063] Source: Technical Referenced File, 1st Edition CAPSUGEL - Coni-Snap Capsules

[0064] Different capsules containing peanut paste and an excipient are formulated according to any method well known to those skilled in the art.

[0065] [Table 2]

[0066] Examples of capsule composition according to the invention Dosage (mg) Peanut Paste (mg per capsule) Tricalcium Phosphate (mg per capsule) Lactose (mg per capsule) Capsule Size 10 10.43 20.86 90 4 20 20.86 41.72 50 4 40 41.72 41.72 20 3 80 83.44 83.44 0 3 160 166.88 166.88 0 0 250 260.75 260.75 100 00 300 312.9 312.9 0 00 500 521.5 180 100 00

[0067] The protein content of peanut paste is quantified from samples of raw, unroasted peanut. This makes it possible, on the one hand, to make the reserve proteins contained in the seed accessible for extraction and, on the other hand, to avoid Maillard reactions which are harmful to the assay. The protein extracts are then quantified by the bicinchoninic acid method. For the Arachis hypogeae L used, the composition of the main allergens in the peanut paste was analyzed and quantified by the Elisa method. It amounts to 12%, 15% and 6% respectively for the levels of Ara h 1, Ara h 3 and Ara h 2.

[0068] [Table 3]

[0069] Contents of allergenic fractions Ara hl, Ara h2 and Ara h3. Dosage (ni g) Ara hide paste Protein ( mg) Ara h 1 (ni g) Ara h 3 (ni g) Ara h 2 (ni g) Capsule size (mg per g Iule) 10 10.43 '? 9 0.26 0.33 0.13 4 20 20.86 4.38 0.53 0.66 0.26 4 40 41.72 8.76 1.05 1.3 0.53 3 80 83.44 17.52 2.1 2.63 1.05 3 160 166.88 35.04 4.2 5.26 2.1 0 250 260.75 54.76 6.6 8.2 3.3 00 300 312.9 65.71 7.9 9.86 3.9 00 500 521.5 109.52 13.1 16.4 6.6 00

[0070] Clinical trial on an adolescent population

[0071] The main objective of the study is to evaluate the efficacy of a peanut desensitization protocol by ingestion of increasing doses of peanut up to a maximum of 2 grams per day. Peanut desensitization will be defined by the absence of objective clinical symptoms after ingestion of a cumulative dose of 2 g of peanut during a Double-Blind Placebo-Controlled Oral Challenge (DBCP) Test (OBCT) at the end of the induction phase of the protocol (OBCT2).

[0072] Choice of the population studied

[0073] Peanut tolerance induction protocols have focused on very heterogeneous populations of children aged 1 to 18 years. To date, the applicant is not aware of any clinical study that has included only adolescents. However, adolescence is a period of particular risk for reactions after accidental ingestion. Indeed, adolescents are less prone to spontaneous recovery than younger children. Furthermore, the use of fixed doses of peanuts, in tolerance induction protocols or diagnostic tests (TPO), are more homogeneous in relation to body surface area.

[0074] The threshold of 500 mg of peanut determines the trace level for a quantity of 1000 g of native food (ftp: / / ftp.fao.org / docrep / fao / 010 / y4705f / y4705f02.pdf). The dose of 2 g, i.e. four times the "trace" threshold, makes it possible to characterize the acquisition of tolerance to traces of peanut. Thus, patients who tolerate the ingestion of 2 g of peanut are assumed to be free from the risk of reaction with a diet containing traces of peanut.

[0075] Description of the research methodology

[0076] The study is multicenter, randomized, double-blind, placebo-controlled, and consists of two phases. Figures 1 and 2 present a synopsis of the progress of the protocol and the methodology used. The first phase is a desensitization phase. Patients receive increasing doses of either placebo or the capsule according to the invention for 24 weeks. Treatment begins at 10 mg / day until reaching 2 g / day, of peanut or placebo, at the end of 24 weeks. The dose is increased in stages, every 14 days. Depending on the occurrence and intensity of the side effects, it is possible to stagnate (14 days) at the dose inducing the side effects.

[0077] The levels are as follows: 10 mg / day, 20 mg / day, 40 mg / day, 80 mg / day, 160 mg / day, 300 mg / day, 500 mg / day, 750 mg / day, 1000 mg / day, 1250 mg / day, 1500 mg / day and 2000 mg / day.

[0078] The use of the capsule according to the invention allows the double blind to be maintained. Thus, the psychogenic effects in the patient that could be associated with taking the allergen as well as the aversion to native peanuts are attenuated. Furthermore, the clinician, who evaluates and grades the side effects, remains objective in his evaluations. Finally, the immune cells of the oral cavity are not solicited.

[0079] The second phase is a maintenance phase. To be eligible for the maintenance phase, patients must tolerate the ingestion of a cumulative dose greater than 2g of peanut at the end of the desensitization phase.

[0080] Oral challenge tests (OCT)

[0081] The TPOs consist of ingesting an increasing dose of peanut, every 30 minutes, up to 5 grams. Within the framework of this protocol, all TPOs will be carried out in DACP, and will allow the maximum tolerated dose to be determined. The reaction during the TPO is defined by the occurrence of an objective clinical manifestation. The blind is lifted after the practice of each TPO, which thus makes it possible to confirm or not the diagnosis of peanut allergy. It is carried out before the desensitization phase (TPO1) and at the end of this 24-week period (TPO2), independently of the tolerance induction protocol with which it has no relation. The expected adverse events are those described as a possible consequence of an oral provocation test. They are listed in Table 4 below.

[0082] [Table 4]

[0083] Adverse effects and authorized treatments Signs Subjective signs Treatment Objective signs Treatment Local Conjunctivitis 2 + 3 Rhinitis; repeated sneezing; nasal obstruction; Watery rhinorrhea 2 + 3 Isolated pruritus: labial, oral, soft palate, pharyngeal 0 or 3 Oral syndrome: velopatine pruritus, lip edema and dysphagia 0 or 3 Dysphagia 0 or 3 Enanthema 3 Uvula edema 3 + 5 Cutaneous Pruritus Isolated 0 or 3 Generalized or Palmoplantar 3 Erythema 0 or 3 Maculopapular rash Urticaria 3 Angioedema 3 + 5 Eczema 11 ± 3 1 Digestive Abdominal pain Isolated 0 or 1 Repeated or associated 0 or 3 Nausea 0 or 1 Vomiting Diarrhea Respiratory Voice changes Laryngeal dyspnea, stridor 3 + 5 Cough, wheezing, dyspnea, asthma attack 4 + 5 FEV1 decrease >15% PEF decrease >20% General Fatigability O or 1 Abnormal pallor 0 Behavioral disorders 0 Pulse rate >20% 0 or 5 Headaches 0 or 1 BP decrease >20 mm Hg Apprehension, refusal to take the next dose 0 or 1 Decrease in SaO2 4 + 5 Malaise 5 + 6 Anaphylactic shock

[0084] The authorized treatments are classified as follows: 1. Therapeutic abstention 2. Symptomatic treatment: emollients or dermocorticoids, antiemetics, antispasmodics, paracetamol 3. Local antihistamines 4. General antihistamines 5. Beta two inhaled mimetics 6. Systemic glucocorticoids 7. Adrenaline

[0085] Anaphylaxis is defined as the rapid onset (a few minutes to a few hours), after exposure to a probable allergen, of symptoms indicating damage to 2 organs (Sampson et al. J. Ail. Clin. ImmunoL, February 2006; 117(2):391-397). For example, the dermatological symptoms involved are pruritus or generalized rash, edema of the lips, tongue or uvula. Respiratory symptoms are dyspnea, wheezing, laryngeal cough, decreased peak expiratory flow and hypoxemia. Digestive symptoms are abdominal cramps, vomiting and diarrhea. General symptoms are a drop in blood pressure or the association of symptoms of organ failure: hypotonia, loss of consciousness, incontinence...

[0086] These symptoms are classified by stage of severity according to the modified Ring and Messmer classification (The diagnosis and management of anaphy Iaxis: an updated practice parameter. J. Allergy Clin. Immunol. 2005; 115:S483-523): “Grade 1: conjunctivitis, rhinitis, oral allergy syndrome, simple generalized urticaria, swelling of the lips and / or face without symptoms of asphyxia (respiratory discomfort), isolated cough or wheezing, nausea or abdominal pain; • Grade 2: Moderate multi-organ involvement with cutaneous and mucosal signs (angioedema) + digestive signs (vomiting, diarrhea) + asthma (acute bronchospasm): cough, dyspnea, wheezing, drop in peak expiratory flow (15% or more of expected or known values) + fatigue and tachycardia; “Grade 3: Severe multi-organ involvement that is life-threatening and requires specific therapy: bronchospasm or signs of laryngeal edema with signs of asphyxia, anaphylaxis (symptoms of multiple organ involvement, including respiratory symptoms) and anaphylactic shock (malaise, agitation, loss of consciousness, collapse), cardiovascular collapse, tachycardia or bradycardia, cardiac rhythm disturbances; and » Grade 4: cardiorespiratory arrest.

[0087] Statistical analysis is performed using STATA12 (StataCorp, College Station, TX) and R (http: / / cran.r-project.org / ).

[0088] Results

[0089] Among the 60 patients tested, 30 patients were included because they had an allergy development threshold of between 100 mg and 2000 mg of peanut. At the beginning of the study, no significant statistical difference appeared between the test group and the control group in terms of age, sex, body mass index, measurement of total and specific IgE dosages, total and specific IgG4, type of reaction observed at diagnosis or number of occurrences of severe reaction after diagnosis, respiratory or food-related pathologies or even medical history.

[0090] Clinical efficacy

[0091] The clinical efficacy results are presented in Table 5. Among the 30 patients included, 28 patients completed the second phase of the oral challenge test, 19 of whom were exposed to peanut and 9 to the placebo. 17 of the 21 patients in the peanut group reached the tolerance threshold of 2 g cumulative peanut. This threshold was reached for only 1 patient out of 9 with the placebo (p < 0.001). A significant increase in the positivity threshold during the TPO was also observed in patients in the treated group (p < 0.001), whereas this threshold did not vary significantly in the placebo group. In addition, the number of patients who quadrupled their tolerance threshold between the first and second phases of the TPO was also significantly higher in patients in the peanut group compared to patients in the placebo group (p < 0.001).

[0092] [Table 5]

[0093] Clinical efficacy .Peanut (n = 19) Placebo (n=9) P TPO2 at 2 g revived Negative * 17 (89%) 1 (11%) <0.001 Positive ** 2(11%) 8 (89%) TPO1 reactivity threshold m; [Q25 Q75] 610 [610-2000] 610 [310-1100] 0.38 TPO2 m; [Q25 Q75] 9000 [4000-9000] 2000 [1100-2000] <0.001 p (TPO2 / TPO1) p <0.001 p -0.02 X4 17 2 < 0.001

[0094] Caption:

[0095] * = patients not tolerating 2 cumulative grams of peanut.** = patients tolerating 2 cumulative grams of peanuts.

[0096] m = average

[0097] Q25 = 1st quantity

[0098] Q75 = 3rd quantity

[0099] Treatment tolerance

[0100] These tolerance results are compiled in Table 6. As can be seen, 2 patients failed to complete the first induction phase. The first patient had to drop out due to moderate adverse effects that required him to repeat a 14-day phase more than 3 times, with the same dose of peanut. The second patient experienced anaphylactic shock 2 hours after taking the peanut capsule, which required the administration of epinephrine and emergency room treatment. In retrospect, the patient admitted to having taken twice the prescribed dose of peanut. No serious reactions or side effects were observed in the control group.

[0101] Moderate adverse events were observed in the same number of patients: 19 / 21 in patients in the peanut group versus 8 / 9 in patients in the control group. However, patients in the peanut group experienced adverse events more frequently than their counterparts in the control group: 6.19 + / -3.17 reactions on average for the peanut group versus 3.66 + / -2.29 reactions on average in the control group (p<0.05). No patient experienced symptoms of esophageal pathology,

[0102] Similarly, the number of patients in the control group who completed a 14-day level without adverse effects was significantly higher than the number of patients in the peanut group (p=0.001).

[0103] In addition, significant differences were also observed in the intensity of adverse events, according to the Ring and Messmer classification. Patients in the control group developed more grade 1 adverse events, while patients in the peanut group experienced more grade 2 and 3 adverse events (p < 0.05).

[0104] Regarding the use of emergency care, no significant difference was observed between the two groups. However, patients in the peanut group experienced significantly more digestive (p<0.01) and respiratory (p=0.01) disorders. than patients in the control group, while systemic and local reactions were, on the other hand, just as significant and numerous between the two groups.

[0105] [Table 6]

[0106] Results of the peanut tolerance induction phase Peanut group Group placed bo N = 21 9 Serious adverse events (AEs) 1 0 ns Withdrawals from the protocol 2 0 ns Number of patients with AEs No 2 1 ns > 1 19 (93.5%) 8 (88.9%) Number of reactions / patient 6.19+3.17 3.66+2.29 p <0.0 5 Number of 2-week steps Without AE 162 / 292 (55. 5%) 88 / 121 (72.7%) p = 0.0 01 With AE 130 / 292 (44. 5%) 33 / 121 (27.3%) Intensity of AE* (n=) 1 93 (72%) 30 (94%) p < 0.0 5 2 32 (25%) 2 (6%) 3 5 (3%) 0 4 0 0 Number of AEs (% of patients in his group) Local 30 (23%) 8 (24%) ns Cutaneous 48 (36%) 16 (48%) ns Digestive 68 (52%) 7 (21%) p<0.0 Respiratory 61(46%) 7(21%) ns Systemic 18 (13%) 2 (6%) ns Treatment of AEs (% of patients in his group) yes 88 (67%) 21 (63%) ns No 42 (32%) 12(36%) Hospitalization for AE 1 0 ns

[0107] Desensitization and immunological modifications

[0108] As can be seen in Table 7, the results of desensitization demonstrate that the patients in the group treated with the capsule according to the invention (Ara group) are significantly more tolerant to peanut than the patients treated with placebo (Plac group). The dermatological skin tests reveal a decrease in the diameter of the allergic reaction from 12.45 + 6.71 mm to 6.05 + 4.06 mm (p < 0.0001) between the two phases of the TPO. Less significant changes were observed in the control group (12.5 ± 6.7mm to 8 ± 3.7mm; p < 0.05).

[0109] In the peanut (Ara) group, the level of serum peanut-specific IgE assays increased significantly throughout this tolerance induction phase (p=0.001). The same kinetics was observed with IgE specific to the allergenic fraction Ara h2. Significant changes in reactivity to the allergens Ara h1 and Ara h2 were observed in patients in the peanut group (p=0.01). In particular, Ara h1-specific IgE assays only reached significant levels in the second phase. In contrast, specific IgE assays for Ara h3, Ara h8 and Ara h9 did not change significantly in patients in the peanut group, compared to their initial level, and were not modified at all in patients in the control group.In patients in the placebo group (Plac), no significant changes were observed for peanut-specific IgE and its various allergenic fractions. Conversely, peanut-specific IgG4 increased significantly in the treated group but not in the placebo group. The same was true for the three main protein fractions Ara hl, Ara h2 and Ara h3.

[0110] [Table?]

[0111] Results of desensitization TPO 1 Induction phase medium TPO 2 m+sd P m+sd P* m+sd p ** P reaction diameter (mm) Ara. 12.4+ 6.7 ns 6.1+4 <0.0001 0.58 Plac. 12.5 +6.5 8+3.8 <0.05 Total IgE (lU / mL) Ara 628+469 ns 698+411 0.357 840+573 0.004 0.014 Plac 1266+1504 1193+1511 0.324 1175+1591 0.264 Peanut Sp. IgE (ÏU / mL) Ara 62.5+34.5 ns 76.0+34.7 0.001 78.6+32.8 <0.001 0.044 Plac 79.0+30.7 78.7+32.9 0.880 79.3+32.1 0.244 Ara hl Sp IgE (ÏU / mL) Ara 33,4+36.6 ns 38.1+39,1 0.227 41.6+38.1 0.011 0.10 Plac 33.6+29.0 31.3+22.0 0.421 28.95+25.0 0.924 Ara h2 Sp IgE (ÏU / mL) Ara 50.4+35.9 ns 63.0+35.6 0.009 62.5+35.0 0,010 0.25 Plac 70.9+34.2 73.44+36.0 3 0.276 71.38+36.8 5 0.105 Ara 113 Sp IgE (ÏU / mL) Ara 24.8+38.5 ns 32.43+4 L6 9 0.160 31.12+38.3 1 0.084 0.20 Plac 23.9+32.9 23.7+31.9 0.881 21.3+31.0 0.528 Ara h8 Sp IgE (ÏU / mL) Ara 1.5+5.2 <0.0 1.2+3.5 0.451 2.2+5.3 0.272 0.06 Plac 17.6+32.6 19.8+33.7 0.421 24.3+33.2 0.126 Ara h9 Sp IgE (ÏU / mL) Ara 0.2+0.7 ns 0,1+0.4 0.743 0.2+0.7 0,650 0.38 Plac 1.0+1.6 0.9+1.5 0.826 1.5+2.8 0.403 Total IgG4 (mg / mL) Ara 0.86+0.84 ns 0.85+0.80 0.217 0.93+0.82 0.240 0.36 Plac 0.83+0.63 0.88+0.73 0.429 0.78+0.59 0.348 PeanutspI gG4 (mg / mL) Ara 0.40+0.45 ns 0.99+0.85 0.303 2.98+3.69 <0.001 0.04 Plac 0.44 + 0.53 0.50 + 0.53 0.458 0.42 + 0.44 0.797 0.036+0.04 0.04+0.05 0.078 0.02+0.02 0.851 Ara 112 sp I gG4 (mg / mL) Ara 0.09+0.10 ns 0.31+0.46 0.627 1.46+2.87 0.003 0.49 Plac 0.08+0.05 0.10+0.08 0.002 0.07+0.06 0.490 Ara h3 sp I gG4 (mg / mL) Ara 0.22+0.40 ns 0.24+0.33 0.787 0.55+0.53 0.0001 0.006 Plac 0.08+0.07 0.12+0.10 0.004 0.09+0.10 0.288 Ara 118 sp I gG4 (mg / mL) Ara 0.01+0.03 ns 0.01+0.04 0.778 0.01+0.058 0.582 0.029 Plac 0.11+0.18 0.11+0.15 0.897 0.17+0.24 0.108 Ara h9 sp I gG4 Ara 0.04+0.13 ns 0.06+0.21 0.849 0.20+0.77 0.146 0.17 Plac 0.34+0.79 0.26+0.55 0.218 0.3+0.57 0.275 . | (mg / mL) | | || || ||

[0112] Caption:

[0113] m± sd = mean ± standard deviation

[0114] Ara - peanut group or group treated with the capsule according to the invention

[0115] Plac = placebo group.

[0116] sp - specific Conclusion

[0117] The peanut capsule according to the invention makes it possible to avoid contact of the peanut composition which it contains with the oral mucosa for various reasons.

[0118] The first reason is that the oral mucosa is rich in antigen-presenting cells, which exposes the risk of allergic reaction, or even anaphylactic shock, and thus limits the possibilities of desensitization. Conversely, the inventors propose to expose the allergen directly to contact with the antigen-presenting cells of the small intestine, the physiological site of the induction of oral tolerance to food antigens, in order to reduce the risks and intensity of allergic reactions during desensitization while maintaining therapeutic efficacy.

[0119] The second reason is that the oral mucosa is the seat of taste and partly of smell. However, peanut has a very characteristic odor and flavor that are difficult to mask. Administration by capsule with intestinal release makes it possible to avoid the nocebo effect, namely that a patient assuming that they are consuming the allergenic substance, triggers an allergic reaction.

[0120] The results of the double-blind clinical trial demonstrate that the administration of the capsule according to the invention makes it possible, on the one hand, to rigorously measure the threshold of reactivity to the allergen by carrying out a double-blind provocation test against placebo, and on the other hand to effectively desensitize the treated patients, while reducing the risk of an allergic reaction occurring in them, particularly the risk of eosinophilic esophagitis and anaphylactic shock.

Claims

Claims

1. A gastrointestinal release capsule in a form suitable for oral administration in a method for desensitizing and / or inducing tolerance in a peanut-allergic subject, said capsule comprising a shell and a core, said core comprising a peanut composition comprising peanut, at least one oil, at least one first powdered excipient, and optionally at least one second prebiotic excipient.

2. Capsule for use according to claim 1, characterized in that the peanuts are roasted peanuts, preferably roasted and non-defatted peanuts.

3. Capsule for use according to any one of the preceding claims, characterized in that said composition comprises between 10 mg and 1000 mg of peanut, preferably between 10 mg and 750 mg of peanut, very preferably between 10 mg and 500 mg of peanut.

4. Capsule for use according to any one of the preceding claims, characterized in that said composition comprises between 5% and 70% of peanut, relative to the total weight of said composition.

5. Capsule for use according to any one of the preceding claims, characterized in that said composition comprises between 10% and 40%, preferably between 10% and 30%, very preferably between 15% and 25%, of allergenic proteins, relative to the total weight of said composition.

6. Capsule for use according to any one of the preceding claims, characterized in that said composition comprises between 10% and 15% of the total proteins for the allergenic fraction Ara hl, between 2% and 10% of the total proteins for the allergenic fraction Ara h2, and between 10% and 20% of the total proteins for the allergenic fraction ARA h3, relative to the total weight of proteins of said composition.

7. Capsule for use according to any one of the preceding claims, characterized in that said oil is sunflower oil.

8. Capsule for use according to any one of the preceding claims, characterized in that said first powdered excipient is tricalcium phosphate; preferably the first powdered excipient is chosen from beta tricalcium phosphate, alpha tricalcium phosphate, and their mixture; alternatively the first powdered excipient is beta tricalcium phosphate or alpha tricalcium phosphate.

9. Capsule for use according to any one of the preceding claims, characterized in that said second prebiotic excipient is lactose, preferably lactose monohydrate.

10. Capsule for use according to any one of the preceding claims, characterized in that said composition comprises between 20 mg and 315 mg of the first powdered excipient, and / or between 0 mg and 100 mg of the second prebiotic excipient.

11. Capsule for use according to any one of the preceding claims, characterized in that said composition comprises between 15% and 55% of the first powdered excipient, relative to the total weight of said composition.

12. Capsule according to any one of the preceding claims, characterized in that said composition comprises between 10% and 75% of the second prebiotic excipient, if present, relative to the total weight of said composition.

13. Capsule for use according to any one of the preceding claims, characterized in that the shell of said capsule is opaque.

14. A capsule for use according to any preceding claim, characterized in that the subject is aged 1 to 18 years.

15. A capsule for use according to any preceding claim, characterized in that the subject is 18 years of age or older.

16. Capsule for use according to any one of the preceding claims, characterized in that the capsule is provided in an unopened form suitable for ingestion, preferably in an unopened form and not mixed with the food bolus.

17. Capsule according to any one of the preceding claims, for use as a medicament in an immunotherapy treatment comprising a desensitization phase and / or induction of a tolerogenic response of the immune system, followed by a maintenance phase and / or maintenance of tolerance.

18. Capsule according to claim 17, being in a form suitable for administration of peanut according to a unit dose comprising an amount of peanut ranging from 10 mg to 2 g, during the desensitization and / or induction phase.

19. Capsule according to one of claims 17 and 18, being in a form suitable for administration of peanut according to a unit dose comprising a quantity of peanut greater than or equal to 2 g, preferably between 2 g and 5 g. during the maintenance and / or tolerance maintenance phase.

20. Capsule according to claim 19, characterized in that the maintenance and / or tolerance maintenance phase is implemented with subjects aged 1 to 18 years tolerating a cumulative dose of peanut greater than 2g.

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