Gastrointestinal release capsule for use in a method for desensitising and/or inducing tolerance in a patient with a peanut allergy

Abstract

Gastro-intestinal release capsule intended for oral use in a method for desensitizing and/or inducing tolerance in a peanut-allergic subject or, alternatively, for diagnosing a peanut allergy in a subject. The capsule has a shell and a core, the core has a composition of peanut including peanut, at least one oil, at least one first pulverulent excipient and, optionally, at least one second prebiotic excipient. The capsule is provided and ingested in an unopened form.

Claims

1. A method for desensitizing and/or inducing tolerance and/or maintaining tolerance in a peanut-allergic subject, the method comprising: orally administering to the subject of at least one gastro-intestinal release capsule, said capsule comprising a shell and a core, said core comprising a peanut composition comprising peanuts, at least one oil, at least one first excipient being a pulverulent excipient, and, optionally, at least one second excipient being a prebiotic excipient; wherein said capsule is provided to the subject in an unopened form and ingested in an unopened form and not mixed into an alimentary bolus.

2. The method according to claim 1, wherein the subject is 1 to 18 years of age or, aged 18 years or more.

3. The method according to claim 1, wherein said method comprises a phase of desensitizing and/or induction of a tolerogenic response of the immune system, followed by a phase of keeping up and/or maintaining the tolerance, wherein said phase of desensitizing and/or induction of a tolerogenic response of the immune system and said phase of keeping up and/or maintaining the tolerance occur concurrently with the step of administering.

4. The method according to claim 3, wherein the phase of desensitizing and/or induction of a tolerogenic response comprises daily administering of said at least one gastro-intestinal release capsule of an average dose of peanut increasing from 10 mg to 2 g during 20 to 28 weeks.

5. The method according to claim 3, wherein the phase of keeping up and/or maintaining tolerance comprises administering a daily average dose of peanut of 2 g to 5 g.

6. The method according to claim 3, wherein the phase of desensitizing and/or induction of a tolerogenic response comprises daily administering of said at least one gastro-intestinal release capsule of an average dose of peanut increasing from 10 mg to 2 g during 24 weeks.

7. The method according to claim 5, wherein the phase of keeping up and/or maintaining tolerance is implemented with subjects aged 1 to 18 years tolerating a cumulated dose of peanut of at least 2 g.

8. The method according to claim 1, wherein the peanuts are roasted and full-fat peanuts.

9. The method according to claim 1, wherein said peanut composition comprises 10 mg to 1000 mg of peanuts.

10. The method according to claim 1, wherein said peanut composition comprises 10 mg to 750 mg of peanuts.

11. The method according to claim 1, wherein said peanut composition comprises 10 mg to 500 mg of peanuts.

12. The method according to claim 1, wherein said peanut composition comprises 5% to 70% of peanuts relative to the total weight of said peanut composition.

13. The method according to claim 1, wherein said peanut composition comprises a proportion of allergen protein between 10% to 40%, relative to the total weight of said peanut composition.

14. The method according to claim 1, wherein said peanut composition comprises a proportion of allergen proteins between 10% to 30% relative to the total weight of said peanut composition.

15. The method according to claim 1, wherein said peanut composition comprises a proportion of allergen proteins between 15% to 25% relative to the total weight of said peanut composition.

16. The method according to claim 1, wherein said peanut composition comprises a proportion of allergen proteins Ara h1 between 10% to 15% relative to the total weight of the proteins of said peanut composition, a proportion of allergen proteins Ara h2 between 2% to 10% relative to the total weight of the proteins of said peanut composition and a proportion of allergen proteins of Ara h 3 between 10% to 20% relative to the total weight of the proteins of said peanut composition.

17. The method according to claim 1, wherein said at least one oil is a sunflower oil.

18. The method according to claim 1, wherein said pulverulent first excipient is tricalcium phosphate.

19. The method according to claim 16, wherein said pulverulent first excipient is chosen from among beta tricalcium phosphate, alpha tricalcium phosphate and their mixture.

20. The method according to claim 17, wherein said pulverulent first excipient is beta tricalcium phosphate or alpha tricalcium phosphate.

21. The method according to claim 1, wherein said prebiotic second excipient is lactose.

22. The method according to claim 19, wherein said prebiotic second excipient is lactose monohydrate.

23. The method according to claim 1, wherein said peanut composition comprises 20 mg to 315 mg of the pulverulent first excipient and 0 mg to 100 mg of the prebiotic second excipient.

24. The method according to claim 1, wherein said peanut composition comprises a proportion of said pulverulent first excipient between 15% to 55% of the total weight of the peanut composition.

25. The method according to claim 1, wherein said peanut composition comprises a proportion of said second excipient, between 10% to 75% of the total weight of said peanut composition.

26. A method of enabling diagnosis of a peanut allergy in a subject, said method comprising: administrating to the subject at least one gastro-intestinal release capsule intended for oral use, said capsule comprising a shell and a core, said core comprising a peanut composition comprising peanut, at least one oil, at least one first excipient being a pulverulent excipient and, optionally, at least one second excipient being a prebiotic excipient, wherein said capsule is provided in an unopened form and ingested in an unopened form and not mixed into an alimentary bolus.

Description

5. LIST OF FIGURES

(1) Other features and advantages of the invention shall appear more clearly from the following description of a preferred embodiment given by way of a simple illustratory and non-exhaustive example, and from the appended figure presenting a block diagram of the progress of the protocol of the clinical study.

(2) FIG. 1 is a first diagram giving a schematic view of the progress of the study.

(3) FIG. 2 is a second diagram giving a schematic view of the progress of the study.

(4) FIGS. 3 and 4 represent the development of the IgG/IgE ratios during the build-up phase.

6. DESCRIPTION OF ONE EMBODIMENT OF THE INVENTION

(5) The general principle of the invention relies on the formulation of capsules comprising peanut paste and the gastro-intestinal release of peanut (ingestion in unopened form) so as to be used, on the one hand, in the reliable and precise diagnosis of peanut-allergy and of the allergy-activation threshold and, on the other hand, in the desensitization of peanut allergy. The formulation in the form of capsules and their ingestion in closed form therefore prevents or at the very least greatly reduces the nocebo effect that could falsify peanut allergy diagnostic tests. It also makes it possible to obtain precise and simple knowledge of the peanut dose administered to the patient. Finally, it facilitates the desensitization protocol for the patient, especially by preventing any contact with the buccal mucosa which is rich in immune cells.

(6) 6.1. Examples of Composition of Capsules According to the Invention

(7) The peanut paste used as a raw material is composed of 95.7% of peanuts, 4.3% of sunflower oil and at least one excipient, namely tricalcium phosphate (a pulverulent excipient) and optionally lactose (prebiotic excipient). Peanut paste is obtained by mixing peanuts 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.

(8) The sizes of the capsules correspond to very precise standards. The shell of each capsule is composed of a head and a body, the body being filled with peanut paste before the head encloses the body.

(9) The capsules according to the invention can be of all sizes, from size 000 (the biggest) to size 4 (the smallest).

(10) TABLE-US-00001 TABLE 1 Detailed view of standards for capsule sizes 000 00 0 1 2 3 4 Length of closed 26.1 23.3 21.7 19.4 18.0 15.9 14.3 capsule (mm) 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 Source: Technical Reference File, “CAPSUGEL - Gélules Coni-Snap” 1st edition

(11) According to all methods well known to those skilled in the art, different capsules are formulated enclosing peanut paste and an excipient.

(12) TABLE-US-00002 TABLE 2 Examples of compositions of capsules according to the invention Tricalcium Peanut paste phosphate Lactose (mg per (mg per (mg per Dosage (mg) capsule) capsule) 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

(13) The protein content of the peanut paste is quantified on the basis of samples of non-roasted raw peanuts. This enables, on the one hand, the reserve proteins contained in the seed to be made accessible for extraction and, on the other hand, the avoidance of Maillard reactions which adversely affect the dosage. The protein extracts are then quantified by the bicinchoninic acid method (the Pierce method, cf. Smith, P. K. et al., Measurement of protein using bicinchoninic acid. Anal. Biochem. 150 (1985) 76-85). For the Arachis hypogeae used, the composition in main allergen fractions of peanut paste has been analyzed and quantified by the Elisa method. This composition amounts respectively to 12%, 15% and 6% for the Ara h 1, Ara h 3 and Ara h 2 content.

(14) TABLE-US-00003 TABLE 3 Allergen fraction Ara h1, Ara h2 and Ara h3 content. Peanut paste Dosage (mg per Protein Ara h 1 Ara h 3 Ara h 2 (mg) capsule) (mg) (mg) (mg) (mg) Capsule 10 10.43 2.2 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

(15) 6.2. Clinical Trial on an Adolescent Population

(16) The main goal 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. Desensitization to peanuts will be defined by the absence of objective clinical symptoms after ingestion of a cumulated dose of 2 g of peanuts during a double blind placebo-controlled (DBPC) food challenge test (FCT) at the end of a phase of induction of the protocol (FCT2).

(17) Choice of the Population Studied

(18) Protocols for the induction of peanut tolerance have taken an interest in very heterogeneous populations of children aged 1 to 18 years. To date, the present applicant is not aware of any clinical study that has included solely adolescents. However, adolescence is a period that is particular risky as regards reaction after accidental ingestion. Indeed, an adolescent is less subject to spontaneous healing than a younger child. Besides, fixed doses of peanuts used in tolerance induction protocols or diagnostic tests (FCT) are more homogenous relative to the body surface area.

(19) The threshold of 500 mg of peanuts determines the state of traces for a quantity of 1000 g of native foodstuff: (ftp://ftp.fao.org/docrep/fao/010/y4705f/y4705f02.pdf). The 2 g dose, namely four times the “trace” threshold, characterizes the acquisition of a tolerance to traces of peanut. Thus, patients who tolerate ingestion of 2 g of peanuts are assumed to be free of risk of reaction to a food diet containing peanut traces.

(20) Description of the Research Methodology

(21) The study is multicenter double-blind, randomized, placebo-controlled approach and consists of two phases. FIGS. 1 and 2 are block diagrams of the progress of the protocol and of the methodology used.

(22) The first phase is a phase of desensitization. The patients receive increasing doses, for 24 weeks, of either placebo or the capsule according to the invention. The treatment starts with 10 mg/day until it reaches 2 g/day of peanuts or placebo at the end of 24 weeks. The increase in the dose is done in stages, every 14 days. Depending on the occurrence and intensity of side effects, it is possible to carry out stagnation phases (of 14 days) in the dose inducing side effects.

(23) The stages are the following: 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 et 2000 mg/day.

(24) The use of the capsule according to the invention makes it possible to maintain the double blind. Thus, this method attenuates the psychogenic effects in the patient that could be associated with the ingestion of allergen as well as aversion to native peanuts. Besides, the practitioner who evaluates and grades the side effects remains objective in his assessments. Finally, the immune cells of the buccal cavity are not affected.

(25) The second phase is a phase of keeping up. To be eligible for the keeping-up phase, the patients must tolerate the ingestion of a cumulated dose greater than 2 g of peanuts at the end of the desensitizing phase.

(26) 6.2.1. Food Challenge Tests (FCT)

(27) The FCTs consist in ingesting an increasing dose of peanuts every 30 minutes up to 5 grams. In the context of this protocol, all FCTs will be carried out in under DACP and will make it possible to determine the maximum tolerated dose. The reaction during FCT is defined by the occurrence of objective clinical manifestations. The double blind is lifted after the practice of each FCT, thus making it possible to confirm or not confirm the diagnosis of peanut allergy. It is carried out before the desensitization phase (FCT1) and at the end of this period of 24 weeks (FCT2), independently of the tolerance induction protocol with which it bears no relationship whatsoever. The expected undesirable events are those described as being a possible consequence of a food challenge test. They are listed in table 4 here below.

(28) TABLE-US-00004 TABLE 4 Adverse events and authorized treatments Signs Subjective signs Treatment Objective signs Treatment Local Conjunctivitis 2 ± 3 Rhinitis, repeated sneezing, nasal 2 ± 3 obstruction, watery nasal discharge Isolated pruritus 0 or 3 Oral allergy syndrome: soft palate 0 ou 3 of the lips, soft prurutis, œdema of the lips and palate and dysphagia pharynx Dysphagia 0 or 3 Enanthema 3 Oedema of the uvula 3 ± 5 Cutaneous Pruritus Isolated 0 or 3 Generalized or palmo-plantar 3 Erythema 0 or 3 Macular-papular rash Urticaria 3 Angio-oedema 3 ± 5 Eczema 1 ± 3 Digestive Abdominal pains Isolated 0 or 1 Repeated or associated 2 0 or 3 Nausea 0 or 1 Vomiting Diarrhea Respiratory Voice alteration 3 Laryngeal dyspnea, stridor 3 ± 5 Coughs, wheezing, dyspnea, acute 4 ± 5 asthma Reduction of FEV>15% Lowering of PF>20% General Tiredness 0 or 1 Abnormal pallor 0 Behavioral 0 Acceleration of pulse >20% 0 or 5 problems Headaches 0 or 1 Lowering of BP>20 mmHg Apprehension, 0 or 1 Lowering of SaO2 4 ± 5 refusal to take the next dose Discomfort 5 ± 6 Anaphylactic shock

(29) The authorized treatments are classified as follows: 0. Therapeutic abstention 1. Treatment of symptoms: emollients or dermocorticoids, anti-emetics, anti-spasmodics, paracetamol 2. Antihistamines by local treatment 3. Antihistamines by general treatment 4. Beta 2 mimetics inhaled. 5. Systemic glucocorticosteroids 6. Adrenalin

(30) Anaphylaxis is defined as the rapid appearance (within a few minutes to a few hours), after exposure to a probable allergen, of symptoms indicating that two organs are affected (Sampson et al. J. All. Clin. Immunol., February 2006; 117(2):391-397). For example, the dermatological symptoms in question are pruritus or generalized rash, oedema of the lips, the tongue or the uvula. Respiratory symptoms are dyspnea, wheezing, laryngeal cough, the reduction of the peak flow and hypoxemia. The digestive symptoms are stomach cramps, vomiting and diarrhea. The general symptoms are a drop in blood pressure or the association of organ failure symptoms: hypotonia, fainting, incontinence, etc.

(31) These symptoms are classified by stage of seriousness according to the modified Ring and Messmer classification (The diagnosis and management of anaphylaxis: an updated practice parameter. J. Allergy Clin. Immunol. 2005; 115:S483-523): Grade 1: conjunctivitis, rhinitis, oral allergy syndrome, simple generalized urticaria, oedema of the lips and/or of the face without symptoms of asphyxia (respiratory discomfort), coughs or isolated wheezing, nausea or stomach pains; Grade 2: moderate multi-organdys function with cutaneous-mucosal signs (angioedema)±digestive signs (vomiting, diarrhea)±asthma (acute bronchial spasm): coughing, dyspnea, wheezing, drop in peak flow (15% or more of the expected or known values)±tiredness and tachycardia; Grade 3: life-threatening severe multiple-organ failure requiring specific therapy: bronchial spasms or signs of laryngeal oedema with signs of asphyxia, anaphylaxis (symptoms of failure in several organs, including respiratory symptoms) and anaphylactic shock (discomfort, agitation, fainting, collapse), cardiovascular collapse, tachycardia or bradycardia, cardiac rhythm disorders; et Grade 4: cardio-respiratory arrest.

(32) Statistical analysis is carried out under STATA12 (StataCorp, College Station, Tex.) and R (http://cran.r-project.org/).

(33) 6.2.2. Results

(34) Among the 53 patients tested, 30 patients have been included because they showed an allergy development threshold of 100 mg to 2000 mg of peanut. At the beginning of the study, no significant statistical difference appears between the test group and the control group in terms of age, sex, body mass index, measurement of total and specific IgE dosages, typeof reaction observed in diagnosis or number of occurrences of severe reactions after diagnosis, respiratory pathologies or pathologies associated with food intake or even in terms of medical history.

(35) Clinical Efficacy

(36) The clinical efficacy results are presented in table 5. Among the 30 patients included, 28 patients followed the second phase of the food challenge test, 19 of them were exposed to peanut and 9 to the placebo. 17 of the 21 patients of the peanut group reached the tolerance threshold ofa cumulated value of 2 g of peanut. This threshold was achieved for only 1 out of 9 patients with the placebo (p<0.001). A significant increase was observed in the threshold of positivity during the FC test among patients of the treated group (p<0.001). This threshold increased 15 times in the treated group and 3 times in the placebo group. In addition, the number of patients whose tolerance threshold quadrupled between the first FC test and the second FC test was also significantly greater among patients in the peanut group than among patients in the placebo group (p<0.001).

(37) TABLE-US-00005 TABLE 5 Clinical efficacy Peanut (n = 19) Placebo (n = 9) p FC test 2 Negative*  17 (89%)   1 (11%) <0.001 at 2 grams Positive**   2 (11%)   8 (89%) Reactivity FCT1 m;  610 [610-2000]  610 [310-1100] 0.38 threshold [Q25 Q75] FCT2 m; 9000 [4000-9000] 2000 [1100-2000] <0.001 [Q25 Q75] p (TPO2/ p < 0.001 p = 0.02 TPO1) X4 17 2 <0.001 Legend: *= patients not tolerating a cumulated value of 2 g of peanut **= patients tolerating a cumulated value of 2 g of peanut m = average Q25 = 1.sup.st quartile Q75 = 3.sup.rd quartile

(38) Tolerance to Treatment

(39) The results for tolerance are compiled in table 6. As can be seen, 2 patients were not able to terminate the first phase of induction. The first patient had to leave the study because of moderate adverse events which obliged him to recommence a 14-day stage more than three times, with the same dose of peanut. The second patient suffered anaphylactic shock two hours after taking the peanut capsule, and had to be given epinephrine and emergency treatment. Subsequently, the patient admitted that he had taken twice the prescribed dose of peanut. No reactions or serious side effects were observed in the control group.

(40) Moderate adverse events were observed among the same number of patients: 19/21 patients in the peanut group against 8/9 patients in the control group. However, patients belonging to the peanut group had more adverse events than those in the control group: 6.19+/−3.17 reactions for the peanut group vs. 3.66+/−2.29 reactions for the control group (p<0.05).

(41) Similarly, the number of patients who terminated a 14-day stage without showing adverse events was significantly greater in the control group than in the peanut group (p=0.001). 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 had more adverse events under grades 2 and 3 (p<0.05).

(42) As regards recourse to emergency treatment, there was no significant difference observed between the two groups. Patients in the peanut group suffered digestive problems (p<0.01) and respiratory problems (p=0.01) in significantly greater numbers than did patients in the control group (68 v. 7, and 61 v. 7 respectively). Adverse oropharyngeal events and dysphagia were rare and were not more frequent in the treated group than in the placebo group (table 6b). No eosinophilic oesophagitis was suspected in the treated group and no patient was excluded because of gastrointestinal symptoms. The general reactions were equally distributed between the placebo group and the treated group. Multiple-organ reactions were rare in the treated group (only one classified as a severe adverse event (SAE) among 19 patients of the patient group) and occurred a minimum of 40 minutes after ingestion of the capsule.

(43) TABLE-US-00006 TABLE 6a Side effects of the peanut tolerance induction phase Peanut Placebo group group p N = 21 9 Severe adverse event 1 0 n.s. (S.A.E.) Exclusion from the 2 0 n.s. protocol Number of patients None 2 1 n.s. with A.E ≥1 19 8 Number of 6.19 ± 3.17 3.66 ± 2.29 <0.05 reactions/patient Number of two-week Without 162/292 88/121 0.001 stages A.E. With A.E. 130/292 33/121 Intensity of A.E.* (n=) 1 93 30 <0.05 2 32 2 3 5 0 4 0 0 n.s. Number of A.E Local 30 8 n.s. Cutaneous 48 16 n.s. Digestive 68 7 <0.01 Respiratory 61 7 0.01 General 18 2 n.s. Treatment of A.E. Yes 88 21 n.s Non 42 12 Hospital treatment for 1 0 n.s A.E

(44) TABLE-US-00007 TABLE 6b Local adverse events (A.E.) during the build-up phase: number of local reactions in brackets: % of patients Local A.E. Peanut (n = 21) Placebo (n = 9) p = Conjunctivitis 10 (24) 2 (22) 0.96 Rhinitis 21 (43) 5 (33) 0.77 Oropharyngeal symptoms  6 (19) 1 (11) 0.71 Dysphagia 0 (0) 0 (0)  ns

(45) Desensitization and Immunological Modifications (Table 7)

(46) The results of the desensitization show that the patients of the group treated with the capsule according to the invention (group Ara) significantly modify their immune balance relative to peanut unlike patients treated with the placebo (group Plac). The cutaneous dermatological tests reveal a reduction 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 FCT phases. Less significant changes were observed in the control group (12.5±6.7 mm to 8±3.7 mm; p<0.05).

(47) In the peanut group (Ara), the level of peanut serum specific IgE dosages increased significantly throughout this phase of tolerance induction (peanut=0.0001). The same kinetics were observed with specific IgE values of the allergen fraction Ara h2. Significant modifications in reactivity to the allergens Ara h1 and Ara h2 were observed among patients of the peanut group (p=0.01). In particular, the specific IgE dosages of Ara h1 attained significant levels only during the second phase. By contrast, the specific IgE dosages for Ara h3, Ara h8 and Ara h9 did not change significantly among patients of the peanut group as compared with their initial level, and were not at all modified among patients of the control group. Among patients of the placebo group (Plac), no significant modification was observed for specific IgE values of peanut as well as for the different allergen fractions. On the contrary, the specific IgG4 values of peanut increased significantly in the treated group but not in the placebo group. This same was the case for the three main protein fractions Ara h1, Ara h2 andAra h3. The ratio between the specific IgG4/IgE antibodies increased significantly between the start and the end of the build-up phase in the peanut group but remained stable in the control group. The increase in this ratio, which indirectly reflects the appearance of desensitization, is significant for the Ara h2 fraction ((p=0.03). (FIGS. 3 and 4).

(48) TABLE-US-00008 TABLE 7 Effects of desensitization on the immunological balance Induction phase medium FCT 2 FCT 1 m ± sd m ± sd m ± sd p (p*) (p**) p** p Diameter Ara. 12.4 ± 6.7  ns 6.1 ± 4   0.58 of the (<0.0001) reaction Plac. 12.5 ± 6.5    8 ± 3.8 (mm) (<0.05)  Total IgE Ara 628 ± 469 ns 698 ± 411 840 ± 573 0.014 (IU/mL) (0.357) (0.004) Plac 1266 ± 1504 1193 ± 1511 1175 ± 1591 (0.324) (0.264) Peanut Ara 62.5 ± 34.5 ns 76.0 ± 34.7 78.6 ± 32.8 0.044 Sp. IgE (0.001) (<0.001)  (IU/mL) Plac 79.0 ± 30.7 78.7 ± 32.9 79.3 ± 32.1 (0.880) (0.244) Ara h1 Ara 33.4 ± 36.6 ns 38.1 ± 39.1 41.6 ± 38.1 0.10 SpIgE (0.227) (0.011) (IU/mL) Plac 33.6 ± 29.0 31.3 ± 22.0 28.95 ± 25.0  (0.421) (0.924) Ara h2 Ara 50.4 ± 35.9 ns 63.0 ± 35.6 62.5 ± 35.0 0.25 SpIgE (0.009) (0.010) (IU/mL) Plac 70.9 ± 34.2 73.44 ± 36.03 71.38 ± 36.85 (0.276) (0.105) Ara h3 Ara 24.8 ± 38.5 ns 32.43 ± 41.69 31.12 ± 38.31 0.20 SpIgE (0.160) (0.084) (IU/mL) Plac 23.9 ± 32.9 23.7 ± 31.9 21.3 ± 31.0 (0.881) (0.528) Ara h8 Ara 1.5 ± 5.2 <0.01 1.2 ± 3.5 2.2 ± 5.3 0.06 SpIgE (0.451) (0.272) (IU/mL) Plac 17.6 ± 32.6 19.8 ± 33.7 24.3 ± 33.2 (0.421) (0.126) Ara h9 Ara 0.2 ± 0.7 ns 0.1 ± 0.4 0.2 ± 0.7 0.38 SpIgE (0.743) (0.650) (IU/mL) Plac 1.0 ± 1.6 0.9 ± 1.5 1.5 ± 2.8 (0.826) (0.403) Total IgG4 Ara 0.86 ± 0.84 ns 0.85 ± 0.80 0.93 ± 0.82 0.36 (mg/mL) (0.217) (0.240) Plac 0.83 ± 0.63 0.88 ± 0.73 0.78 ± 0.59 (0.429) (0.348) Peanut sp Ara 0.40 ± 0.45 ns 0.99 ± 0.85 2.98 ± 3.69 0.04 IgG4 (0.303) (<0.001)  (mg/mL) Plac 0.44 ± 0.53 0.50 ± 0.53 0.42 ± 0.44 (0.458) (0.797) Ara h1 sp Ara 0.04 ± 0.05 ns 0.06 ± 0.07 0.38 ± 0.89 0.12 IgG4 (0.909) (0.026) (mg/mL) Plac 0.036 ± 0.04  0.04 ± 0.05 0.02 ± 0.02 (0.078) (0.851) Ara h2 sp Ara 0.09 ± 0.10 ns 0.31 ± 0.46 1.46 ± 2.87 0.49 IgG4 (0.627) (0.003) (mg/mL) Plac 0.08 ± 0.05 0.10 ± 0.08 0.07 ± 0.06 (0.002) (0.490) Ara h3 sp Ara 0.22 ± 0.40 ns 0.24 ± 0.33 0.55 ± 0.53 0.006 IgG4 (0.787) (0.0001) (mg/mL) Plac 0.08 ± 0.07 0.12 ± 0.10 0.09 ± 0.10 (0.004) (0.288) Ara h8 sp Ara 0.01 ± 0.03 ns 0.01 ± 0.04  0.01 ± 0.058 0.029 IgG4 (0.778) (0.582) (mg/mL) Plac 0.11 ± 0.18 0.11 ± 0.15 0.17 ± 0.24 (0.897) (0.108) Ara h9 sp Ara 0.04 ± 0.13 ns 0.06 ± 0.21 0.20 ± 0.77 0.17 IgG4 (0.849) (0.146) (mg/mL) Plac 0.34 ± 0.79 0.26 ± 0.55  0.3 ± 0.57 (0.218) (0.275) Legend: m ± sd = average ± mean standard deviation Ara = peanut group or group treated by the capsule according to the invention Plac = placebo group sp = specific
FIGS. 3 and 4 represent the progress of the IgG/IgE ratios during the build-up phase. In FIG. 3 (ratio of specific to peanut IgG4/IgE), we observe an increase (peanut=0.06) in the ratio of the IgG4 (μg/mL)/IgE antibodies (IU/mL) specific to peanut between FCT1 and FCT2. In FIG. 4, we observe a significant increase (p=0.03) of the ratio of the specific IgG4 (μg/mL)/IgE (IU/mL) antibodies of the Ara h2 fraction of peanut between FCT1 and FCT2.

7. CONCLUSION

(49) The peanut capsule and its ingestion in closed (unopened) form according to the invention prevents contact between the peanut composition that it contains and the buccal mucosa for different reasons.

(50) The first reason is that the buccal mucosa is rich in antigen-presenting cells: this exposes the patient to allergy risks or even anaphylactic shock and thus limits the possibilities of desensitization. Conversely, the inventors propose to expose the allergen by putting it into direct contact with the antigen-presenting cells of the small intestine which is the physiological site of the induction of oral tolerance to food antigens, in order to reduce the risks and intensity of allergy reactions during desensitization while maintaining therapeutic efficacy.

(51) The second reason is that the buccal mucosa is the site of taste and partly of smell. Now peanut has a very characteristic smell and taste that are difficult to mask. Administering capsules with intestinal release prevents the nocebo effect, namely an effect where a patient assumes that the is in the process of consuming the allergic substance and triggers an allergy reaction.

(52) The results of the double blind clinical trial show 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 placebo-controlled food challenge test and, on the other hand, to efficiently desensitize the treated patients while reducing the risks of the occurrence of allergy reactions among them, especially the risks of eosinophilic oesophagitis and anaphylactic shock.

(53) An exemplary embodiment of the invention overcomes the drawbacks of the prior art, especially in terms of acceptability, efficiency and security by reducing side effects and/or adverse events.

(54) More specifically, at least one embodiment provides a composition that can be used to desensitize and/or induce tolerance among peanut-allergic subjects.

(55) An exemplary embodiment proposes a method for diagnosing an allergy in a subject.

(56) An exemplary embodiment proposes a composition for exhaustively and definitively desensitizing a peanut-allergic subject.

(57) An exemplary embodiment proposes a composition for use in a method for desensitizing and/or inducing tolerance in a peanut-allergic subject, while at the same time efficiently masking the taste, color and odor of peanut, thus eliminating food aversion to this allergen.

(58) An exemplary embodiment proposes a composition for use in a method for desensitizing and/or inducing tolerance in a peanut-allergic subject, by reducing the side effects, especially the risk of oral-pharyngeal reactions (oral syndromes), eosinophilic oesophagitis, anaphylactic reactions and other adverse effects or events.

(59) An exemplary embodiment proposes a method for making a composition for use in a method for desensitizing and/or inducing tolerance in a peanut-allergic subject, while minimizing the occurrence of the nocebo effect.

(60) An exemplary embodiment proposes a composition intended for use in a method for desensitizing and/or inducing tolerance in a peanut-allergic subject aged 1 to 18 years.

(61) Although the present disclosure has been described with reference to one or more examples, workers skilled in the art will recognize that changes may be made in form and detail without departing from the scope of the disclosure and/or the appended claims.