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Oral immunotherapy for food allergy

Oral immunotherapy for food allergy
Author:
Anna Nowak-Węgrzyn, MD, PhD
Section Editor:
Scott H Sicherer, MD, FAAAAI
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Feb 2022. | This topic last updated: Jan 28, 2022.

INTRODUCTION — Management of food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. Oral immunotherapy (OIT) is one of several allergen-specific approaches under investigation for the treatment of food allergy (table 1) [1]. The ultimate goal of OIT and other therapeutic approaches to food allergy is to induce permanent tolerance to the food, where allergic reactions will not recur upon reexposure after a period of abstinence. However, none of the available treatments or those in phase-III trials appear to achieve permanent tolerance in a substantial number of treated patients (figure 1 and table 2). (See "Management of food allergy: Avoidance" and "Food-induced anaphylaxis" and "Anaphylaxis: Emergency treatment".)

OIT for food allergy is reviewed in this topic. Other food allergen-specific therapies, as well as nonspecific therapies for food allergy, are reviewed separately. (See "Investigational therapies for food allergy: Immunotherapy and nonspecific therapies".)

OVERVIEW — OIT to food is a major focus of investigation in the treatment of food allergy. However, studies have yet to demonstrate the ability to cure food allergy (and induce true tolerance). Furthermore, allergic reactions to OIT are common and occur at higher rates in patients on OIT than those avoiding the food. Many unanswered questions remain, and additional long-term follow-up data are needed to help determine in which patients the benefits may outweigh the risks.

The 2014 Updated Food Allergy Practice Parameter advised against performing OIT in routine clinical practice [2]. The 2017 European Academy of Allergy and Clinical Immunology (EEACI) Task Force on Allergen Immunotherapy and the 2016 guidelines from the Japanese Society of Pediatric Allergy and Clinical Immunology recommended conducting OIT in medical facilities with expertise in allergen immunotherapy and management of anaphylactic shock [3,4]. The Japanese guidelines additionally stated that OIT should not be recommended as standard treatment. The US Food and Drug Administration (FDA) approved of the first biologic drug for peanut OIT in children 4 to 17 years old in January 2020, with the indication of "the mitigation of allergic reactions, including anaphylaxis that may occur with accidental exposure to peanut." Revised guidelines regarding the use of OIT are anticipated.

Rationale and mechanisms of action — The rationale for using the oral route is that ingestion of a food antigen by someone not allergic to that food preferentially results in an active immune system response that does not trigger an allergic reaction towards that antigen (ie, oral tolerance) [5,6]. Oral tolerance is thought to be mediated by induction of regulatory T cells with low-dose antigen exposure or lymphocyte anergy or deletion with high antigen doses (figure 1). (See "Pathogenesis of food allergy", section on 'Factors influencing sensitization or tolerance'.)

The humoral immunologic changes associated with OIT include a gradual increase in serum levels of specific immunoglobulin G4 (IgG4), immunoglobulin A (IgA), and immunoglobulin A2 (IgA2) [7,8]. In addition, an initial increase in serum levels of specific immunoglobulin E (IgE) antibodies is seen in the first 12 months, followed by a subsequent decrease. Specific T regulatory cells increase and peak at approximately 12 months, with a subsequent decrease. Increased antigen-induced regulatory T cell function is associated with hypomethylation of forkhead box protein 3 (FOXP3) [9].

Basophil reactivity, skin prick test responses, and serum levels of T helper type 2 (Th2) cytokines decrease gradually, whereas interferon (IFN) gamma, macrophage inflammatory protein (MIP) 1 alpha, and monocyte chemotactic protein (MCP) 1 increase over the course of OIT [10-13].

Goals — The ultimate goal of treatment for food allergy is to induce permanent tolerance to the food, such that there can be periods of abstinence that do not lead to a recurrence of clinical reactivity upon reintroduction of the food (table 2) [1,6]. However, because achieving permanent tolerance to the food with OIT has proved elusive in most studies of food allergy treatments, the goal of most available treatments is to increase the amount of food persons with food allergies are able to consume before they experience symptoms. Increasing the allergic threshold may prevent reactions that occur due to accidental exposures to that particular food. Additionally, burdensome lifestyle changes as well as anxiety about the possibility of anaphylaxis and death are some of the main causes of morbidity in food allergy. Important goals for patients and their caregiver(s) are to reduce this anxiety and improve quality of life (QOL) [14]. (See "Food allergy: Impact on health-related quality of life".)

Tolerance versus desensitization — Oral tolerance is a permanent state of antigen nonresponsiveness, even when exposure is infrequent (table 2). However, it is unclear what time period of food allergen elimination followed by subsequent safe reexposure defines permanent tolerance to that food. Thus the surrogate for permanent tolerance used by many clinical trials is "sustained unresponsiveness" (SU) to the food after an interval of sustained treatment followed by removal of the food from the diet over a defined period of time, typically weeks to months. Desensitization, in contrast, is defined as an increase in reaction threshold to a food allergen while receiving active therapy, similar to that achieved with drug desensitization. The primary outcomes typically measured in OIT studies are desensitization and sometimes SU. Desensitization to an arbitrarily chosen dose of food, ranging from a small portion (eg, 300 mg) to a regular serving size of the food, is tested with an oral food challenge (OFC) while continuing maintenance dosing. SU is tested with an OFC to the food following discontinuation of OIT for a period of time, varying from 2 to 52 weeks (usually 4 to 16 weeks).

General protocol — Patients are typically started on a very small daily dose of the food (eg, 3 to 6 mg of food protein) and advanced periodically (usually every two weeks) to a maintenance dose (eg, 300 mg or, depending on the food and goals, 1 to 2 g of food protein daily) over several months. The initial dose and each dose increase are given under clinical supervision (usually with a 60-minute observation period following the dose administration), whereas the remainder of the daily doses during the dose advancement phase and maintenance therapy are administered at home. OIT doses are typically administered at the same time of the day (evening is preferred for home administration), following a meal or large snack. The food included in OIT is almost always otherwise strictly avoided in the diet for the duration of OIT. Each patient treated with OIT is also prescribed an epinephrine autoinjector, instructed in its use, and given a detailed emergency anaphylaxis treatment plan.

Minimizing risk of systemic reactions — A number of general and specific measures are recommended to minimize the risk of systemic reactions related to OIT dosing. Cofactors that increase the risk of an allergic reaction include exercise or hot water exposure (hypermetabolic state with elevation of body temperature), intercurrent illness (eg, viral infection), fasting or dosing on an empty stomach, menstruation, sleep deprivation, and use of nonsteroidal antiinflammatory drugs (NSAIDs) [15-18]. Timing of dosing is adjusted to avoid these cofactors. Hot showers or baths, for example, should be avoided immediately prior to or within three hours of taking the dose, and physical activity should be restricted for one to two hours after dosing.

If avoidance of any of these cofactors is not possible, the dose is temporarily withheld, as in the case of active illness, or decreased. However, reactions may occur during a prodromal phase of an infection before any symptoms of an illness become apparent. Dosing is also adjusted, or the treatment discontinued, in patients with chronic or recurrent allergic gastrointestinal symptoms or anaphylaxis. Additional indications for discontinuation of therapy include inability to tolerate less than a 3 mg dose, nonadherence with daily dosing, suspected eosinophilic esophagitis, recurrent asthma exacerbations, or persistent loss of asthma control.

When dosing is temporarily withheld or one or more doses are missed, dosing is either resumed at the same dose at home or under supervision in the office, or the dose is reduced and gradually escalated to preillness level, depending upon the number of missed doses.

Efficacy and adverse effects — None of the available evidence shows that OIT can induce permanent tolerance, and, for most allergens, only a minority of children treated with OIT appear to achieve SU (table 2). In addition, most studies have shown no difference in improved health-related quality of life (HRQL) or only improvement in parental, but not child, HRQL.

Approximately 40 to 75 percent patients treated with OIT do pass a supervised challenge to a larger amount of the food allergen while on maintenance therapy than at baseline and are considered at least partially "desensitized." Desensitization in this setting is defined as a state of temporary food allergen hyporesponsiveness with an increased threshold for reactions compared with the pre-OIT threshold. The cut-off for an increased threshold (eg, percentage or amount tolerated compared to baseline) that defines hyporesponsiveness is not standardized and varies from study to study.

Theoretically, this desensitization should protect against reactions to accidental ingestion of similar or lower amounts of the food that were tolerated in the supervised challenge. However, despite the ability of OIT to induce desensitization, significant acute allergic reactions to the therapy and/or accidental exposures are still common in treated patients and can occur even on maintenance dosing. Higher rates of anaphylaxis and use of epinephrine are consistently seen in the treatment groups compared with avoidance alone [19]. In addition, rates of other types of allergic reactions (eg, gastrointestinal symptoms, angioedema, wheezing, and eosinophilic esophagitis) are common and are typically higher in patients treated with OIT.

It is possible that OIT does provide some protection against reactions due to accidental ingestion, but the effect may be negated by reactions to daily OIT dosing due to a lowered reaction threshold (eg, illness, exercise) or reactions to larger accidental exposures if avoidance is not as careful due to the perceived protective effect of OIT. In addition, limited long-term follow-up data suggest that desensitization may not be maintained in a number of patients, even with daily exposure.

Most of the above data are from peanut OIT trials, with fewer data for other allergens. OIT outcomes for individual foods are discussed in greater detail below. (See 'Single-food OIT' below.)

SINGLE-FOOD OIT — Multiple OIT protocols have been reported for peanut, cow's milk (hereafter referred to in this topic as "milk"), and hen's egg (hereafter referred to in this topic as "egg"), with more limited studies for wheat [20-25] and sesame [26] and only case reports for other foods such as fish [27,28], apple [27,28], orange [27], and celery [29]. The most extensively studied foods are reviewed here.

Peanut — In the available clinical trials, peanut OIT consistently increased the rate of allergic reactions, including anaphylaxis requiring treatment with epinephrine. This occurred despite OIT increasing supervised food challenge thresholds (ie, inducing at least partial desensitization to peanut) in a clinical setting, a surrogate measure of preventing reactions to accidental exposures in a real-world setting. Many patients are unlikely to be good candidates for peanut OIT, either because they already have a threshold that is high enough to make accidental ingestion reactions unlikely [30] or because the adverse effect profile and daily commitments required for therapy outweigh any potential benefit of increasing the reaction threshold. (See 'Efficacy' below and 'Adverse events' below.)

Despite the increased risk of anaphylaxis and other adverse effects, some patients may be highly motivated to try OIT in the hope that it may alleviate some of the anxiety and fear of experiencing a severe allergic reaction in the event of accidental peanut ingestion. For such patients, it is important to provide accurate information on the anticipated effects of OIT, particularly that it does not reduce the risk of anaphylaxis (in fact, it increases the risk) and that, based upon the available data, it does not appear to improve quality of life (QOL).

If OIT is undertaken, appropriate safety precautions are critical. A Risk Evaluation and Mitigation Strategy (REMS) that includes requirements to assure safe use and minimize risk of anaphylaxis is part of the US Food and Drug Administration (FDA) approval for a peanut allergen oral immunotherapy powder because of the increased rate of anaphylaxis reported in treated patients in clinical trials. Recommendations include continued avoidance of peanut in the diet, immediate availability of injectable epinephrine at all times, and supervised initial dose escalation and up-dosing in a health care setting with clinicians trained and equipped to manage severe allergic reactions. Both the clinician who prescribes the peanut allergen powder and the health care setting in which it is administered must be certified through the REMS program. OIT with peanut allergen powder is contraindicated in patients with uncontrolled asthma or a history of an eosinophilic gastrointestinal disorder.

Efficacy — Several randomized trials [31-37] and a number of uncontrolled studies [9,38-43] have demonstrated that peanut OIT is highly effective in inducing desensitization in a clinical setting, but it increases, rather than decreases, the rate of allergic reactions in the real-world setting (see 'Adverse events' below). Short-term sustained unresponsiveness (SU) after discontinuing OIT is much less common than desensitization. Data suggest that the development of SU is dose and duration dependent and may also be influenced by the severity of peanut allergy and how early in life OIT is started [31]. Longer-term SU is even rarer, and data suggest that ongoing exposure is necessary to maintain the protective effect [44]. The available evidence also suggests that peanut OIT does not improve QOL for the patient. In addition, there are considerable burdens and costs associated with peanut OIT.

In a meta-analysis of 12 trials (1041 patients), peanut OIT increased the likelihood of passing an in-clinic food challenge compared with an elimination diet alone (40 versus 3 percent; relative risk [RR] 12.4, 95% CI 6.8-22.6) [19]. However, OIT increased the risk of anaphylaxis during the maintenance phase (22 versus 7 percent; RR 3.1, 95% CI 1.8-5.6), increased need for epinephrine (8.2 versus 3.7 percent; RR 2.2, 95% CI 1.3-3.8), increased the frequency of vomiting and other gastrointestinal symptoms (33 versus 19 percent; RR 1.8, 95% CI 1.4-2.4), and increased other adverse events (see 'Adverse events' below). In the four trials that assessed QOL, parent/caregiver- and patient-reported QOL scores were similar in both groups. The trials included in the meta-analysis varied with respect to the OIT formulation and dosing protocol used. However, in subgroup analysis, the findings were consistent irrespective of OIT protocol and whether or not a proprietary formulation or readily available peanut flour was used.

A specific preparation of peanut allergen oral immunotherapy powder containing consistent quantities of the major peanut (Arachis hypogaea, Ara h) proteins (Ara h 1, Ara h 2, and Ara h 6) was approved in 2020 by the US FDA for patients 4 to 17 years of age with a confirmed peanut allergy (patients who start therapy at ≤17 years of age may continue therapy as an adult) [45,46]. US FDA approval was based upon the largest trial of this therapy, which included 499 children aged 4 to 17 years and 56 adults aged 18 to 55 years [35]. This trial was included in the above meta-analysis. Patients were considered to have passed the exit peanut challenge even if they had mild symptoms. Of the children randomly assigned to active treatment (300 mg/day of peanut protein), 77 percent tolerated the 300 mg dose, and 67 percent were able to ingest ≥600 mg of peanut protein (equivalent to approximately two peanut kernels) with no more than mild symptoms at the exit peanut challenge compared with 4 percent in the placebo group. Nearly all patients reported adverse events during the study. Moderate-to-severe exit challenge-associated symptoms were lower in the treatment group compared with placebo. However, the rate of serious or severe adverse events during the study was higher in the active treatment group compared with placebo (6 versus 2 percent, respectively) as was the rate of epinephrine administration (14 versus 6 percent, respectively). In addition, considerably more patients in the OIT group withdrew from the trial due to adverse events compared with the placebo group (16 versus 2 percent). One patient in the treatment group was diagnosed with eosinophilic esophagitis. Changes in QOL were not examined.

Limited randomized trial and observational data suggest that OIT may be better tolerated and perhaps more effective in young children than it is in older children. As part of a larger trial, 146 children <4 years of age (median age 39.3 months) were randomly assigned to peanut OIT (n = 96; minimum daily maintenance dose target 250 mg, maximum 2000 mg) or placebo (n = 50) [37]. After 104 weeks on maintenance therapy, 68 of 96 (70.8 percent) and 1 of 50 (2 percent) in the peanut OIT and placebo groups, respectively, passed the 5000 mg peanut double-blind, placebo-controlled food challenge (DBPCFC) at week 134 and were considered desensitized (risk difference [RD] 69 percent, 95% CI 59-79 percent). The mean peanut dose tolerated in the DBPCFC was 5005 mg in the peanut OIT group and 5 mg in the placebo group. After 26 weeks of avoidance, 20 children (20.8 percent; 29.4 percent of those desensitized, intention to treat [ITT] analysis) versus 1 child (2 percent; same patient that was desensitized) in the treatment and placebo groups, respectively, passed the DBPCFC and were considered in "remission," the term applied for SU at six months in this study (RD 19 percent, 95% CI 10-28%). The median peanut dose tolerated in the DBPCFC was 755 mg in the peanut OIT group and 0 mg in the placebo group. In a prospective study of 40 young children (ages 9 to 36 months) treated with either high- or low-dose peanut OIT (300 mg or 3000 mg peanut protein), both groups demonstrated high rates of short-term SU (78 percent overall) after four weeks of avoidance following the maintenance dosing phase [31]. Nearly all patients experienced mild or moderate adverse events, but serious adverse events were not reported. Of the 32 children with short-term SU who were instructed to continue peanut in the diet ad lib, 27 reported continued peanut consumption after a mean follow-up of 65 months since completion of the initial study [47].

However, the effect of OIT appears to wane once therapy is discontinued (ie, it does not appear to induce long-term SU in most patients). This was demonstrated in the Peanut Oral Immunotherapy Study: Safety, Efficacy, and Discovery (POISED) trial, in which 120 patients with peanut allergy were randomly assigned in a three-way fashion to two years of high-dose peanut OIT (daily dose of 4000 mg) followed by one year of no OIT (group 1, n = 60), two years of high-dose peanut OIT followed by one year of low-dose OIT (daily dose of 300 mg; group 2, n = 35), or three years of placebo (n = 25) [44]. At the two-year mark, 84 percent of patients in the active therapy groups (groups 1 and 2) were able to pass a 4000 mg peanut challenge compared with 4 percent in the placebo group. However, the ability to pass the challenge declined considerably during the final year of the trial after stopping or reducing the dose of OIT. At the three-year mark, the rate of passing the peanut challenge among patients who had stopped taking OIT (group 1) was 13 percent, which was not statistically different than the 4 percent rate in the placebo group. Among patients who continued on low-dose OIT (group 2), 37 percent passed the challenge at the three-year mark.

Adverse events — Despite high rates of desensitization, studies have consistently shown an increased risk of allergic reactions including anaphylaxis in patients on OIT compared with avoidance alone. In patients on OIT, these allergic reactions may occur with OIT dosing (up-dosing and maintenance therapy) or with accidental exposures.

A systematic review and meta-analysis of peanut OIT that included 12 trials with a total of 1041 patients with peanut allergy found that those on OIT had a higher anaphylaxis risk (RR 3.12, 95% CI 1.76-5.55, RD 15.1 percent), anaphylaxis frequency (incidence rate ratio [IRR] 2.72, 95% CI 1.57-4.72, RD 12.2 percent), and epinephrine use (RR 2.21, 95% CI 1.27-3.83, RD 4.5 percent) than those not on OIT (avoidance/placebo) during both the build-up and maintenance phases of dosing despite having a greater likelihood of passing a supervised challenge (RR 12.42, 95% CI 6.82-22.61) [19]. In a retrospective review of peanut OIT administered at five different sites, reactions treated with epinephrine occurred at a rate of 0.7 per 1000 escalation doses and 0.2 per 1000 maintenance doses [48].

Patients on OIT are also at increased risk for nonanaphylactic allergic reactions including vomiting, angioedema, and upper and lower respiratory tract reactions [19]. In addition, there are case reports of patients developing eosinophilic esophagitis on peanut OIT [49]. No difference in QOL was found between the groups in the meta-analysis (RR 1.21, 95% CI 0.87-1.69) [19].

Reactions are more common with the initial escalation and up-dosing but can also occur with home dosing, including maintenance therapy. In one small study, the risk of a reaction with any home dose was 3.5 percent, and treatment was given for 0.7 percent of home doses [39]. Approximately 6 to 16 percent of subjects on peanut OIT withdraw from clinical trials due to allergic symptoms [32,33,39]. Treatment-limiting side effects are especially common with high-dose OIT. This was demonstrated in one trial in which only 21 percent of children treated with peanut OIT reached the target dose of 5000 mg peanut protein, primarily due to a distaste for peanuts and unacceptable adverse events [36]. Anaphylaxis during up-dosing occurred in 19 percent of children, and 24 percent discontinued OIT, mostly due to adverse events.

Cow's milk — Milk OIT is similar to peanut OIT in that it is also effective in inducing in-clinic desensitization but increases the risk of allergic reactions, although clinical trial data are more limited and there are no approved formulations. A significant challenge in determining the efficacy of therapies for milk and egg allergies is that the natural rate of resolution of these allergies is much higher than for peanut. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

In a 2012 meta-analysis of five milk OIT trials (218 children), milk OIT increased the likelihood of developing full tolerance to milk by 10-fold (95% CI 4.1-24.2) and partial tolerance by fivefold (95% CI 1.2-24.5) compared with a milk elimination diet alone [50]. However, the risk of an adverse reaction was 34-fold higher (95% CI 4.8-244.7) in children receiving OIT compared with an elimination diet alone, and OIT also increased the likelihood of experiencing laryngospasm (RR 12.9, 95% CI 1.7-99) or wheezing (RR 3.8, 95% CI 2.9-5) and needing epinephrine treatment (RR 5.8, 95% CI 1.6-22) or glucocorticoid therapy (RR 11, 95% CI 2.7-46). A separate 2012 meta-analysis had similar findings and noted that 1 in every 11 patients on milk OIT was treated with epinephrine [51].

There is one case report of life-threatening anaphylaxis in a patient during the dose-escalation phase of milk OIT when dose escalation was continued despite a serious reaction that occurred earlier on the same day [52]. In addition, several patients have developed eosinophilic esophagitis on milk OIT [53,54]. Furthermore, in one of the few long-term follow-up studies of OIT, only 6 of 32 patients (19 percent) who had successfully completed a milk OIT trial had unlimited intake of milk and other dairy products, and, among those six patients, half reported variable symptoms with ingestion [55].

Hen's egg — Egg OIT, as with OIT for other foods, appears to be effective in desensitizing most patients in a clinical challenge setting [56]. SU is induced less frequently than desensitization but occurs at a higher rate in egg OIT-treated patients than in patients who follow a strict egg elimination diet [57]. Results from one study suggest that longer duration of therapy may increase the rate of SU [58]. However, a significant challenge in determining the efficacy of therapies for milk and egg allergies is that the natural rate of resolution of these allergies is much higher than for peanut. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

In one randomized trial, 55 children aged 5 to 11 years (median age 7 years) received either egg-white powder OIT with a maintenance dose goal of 2 grams (n = 40) or placebo (n = 15) [8]. Egg was otherwise avoided by all subjects. All completed the initial day of dose escalation, but 13 percent withdrew before the maintenance phase (two placebo and five in OIT group). Twenty-two children (55 percent) in the OIT group passed the challenge (5 grams of egg-white powder, approximately equivalent to one large egg [6 grams of protein]) at 10 months and were considered desensitized compared with none in the placebo group. The rates of adverse events associated with OIT doses were highest during the first 10 months of OIT, occurring with 25 percent of OIT doses compared with 4 percent of placebo doses. Oropharyngeal symptoms occurred in 78 percent of patients on OIT compared with 20 percent in the placebo group. No severe adverse events occurred.

In an unblinded extension of the study, the OIT group continued on maintenance dosing, and the placebo group continued complete egg avoidance until the second challenge with 10 grams of egg-white powder at 22 months. Thirty children (75 percent) in the OIT group passed the 22-month oral food challenge (OFC), and the one eligible child in the placebo group (egg white-specific IgE <2 kU/L) failed the challenge. The other children in the placebo group were considered still allergic to egg (egg white-specific IgE ≥2 kU/L). SU after two months of egg avoidance was demonstrated in 11 of 29 patients (27.5 percent of the original 40 on OIT). Egg was introduced into the diet ad libitum in these children, and no adverse events were noted at 30 and 36 months of follow-up. Children who did not achieve SU continued egg OIT with no change in the rate of desensitization noted over time [58]. However, an increase in the rate of SU was seen such that 20 children in total (50 percent of the original 40) developed SU by year 4. This compares with a rate of natural resolution of the allergy of 27 percent (4 of 15) in the placebo group. In year 5, 16 percent (3 of 19) of children who achieved SU reported mild, primarily oral symptoms with concentrated egg ingestion, but none reported symptoms with baked egg ingestion [59]. Similar findings were reported in several observational studies [60-63], although egg OIT was not found to expedite the natural acquisition of tolerance in one randomized but unblinded study [18].

Wheat — Five small pilot studies of wheat OIT in children reported variable success with desensitization and some problems with adherence [20-24]. One potential hurdle with wheat OIT that may affect adherence is the larger volume that patients must consume because of the relatively lower amount of protein in wheat compared with milk, egg, or peanut. A randomized trial using high protein-content vital wheat gluten (VWG) rather than more standard forms of wheat for OIT demonstrated desensitization and SU, although at lower rates than that seen for other foods [25]. However, it is not possible to directly compare the outcomes among clinical trials of food OIT, because of heterogeneity of study design, including the maintenance doses used, duration of treatment, and primary endpoints examined.

In this trial, 46 patients aged 4 to 22 years with wheat allergy confirmed by DBPCFC were randomly assigned to lower-dose VWG OIT (maximum daily dose 1445 mg wheat protein) or placebo [25]. DBPCFC (up to a cumulative dose of 7443 mg wheat protein, equivalent to two to three slices of bread) was performed at the end of year 1. Patients on lower-dose OIT continued dosing for another year, followed by an on-therapy DBPCFC and an off-therapy DBPCFC if they passed the on-therapy challenge. Patients on placebo crossed over to higher-dose VWG OIT (maximum daily dose 2748 mg wheat protein) and underwent DBPCFC at the end of year 2. At the end of the first year, 52 percent of the lower-dose group tolerated at least 4443 mg of wheat protein on DBPCFC compared with no patients in the placebo group. At the end of the second year, 30 percent of the lower-dose OIT group and 57 percent of the crossover higher-dose OIT group tolerated the full dose (7443 mg wheat protein) on DBPCFC, and three patients (13 percent) in the lower-dose group demonstrated SU on DBPCFC 8 to 10 weeks after cessation of therapy. Adverse reactions were three times more common in the lower-dose OIT group than placebo (15.4 versus 5.8 percent). Eleven percent of patients on active therapy withdrew due to dosing-related symptoms (predominantly gastrointestinal), and 0.08 percent of doses resulted in treatment with epinephrine.

Sesame — One study has examined the safety and efficacy of sesame OIT. In this study, 60 patients (median age 7.5 years) with sesame allergy confirmed by OFC underwent sesame OIT (target dose 4000 mg sesame protein, minimum dose 240 mg sesame protein [equivalent to 1 gram of tahini]) [26]. At the end of the build-up phase, patients were switched to a daily maintenance dose of 1200 mg sesame protein, equivalent to 5 grams (1 teaspoon) of tahini, or the highest tolerated amount if <1200 mg. Fifteen sex- and age-matched patients with sesame allergy (positive OFC or history of a recent reaction with positive in vitro or skin prick testing) who continued avoidance served as observational controls. The median time to reach the maintenance dose was 6.5 months. Full desensitization to 4000 mg sesame protein was achieved at the end of the build-up phase in 53 patients (88.3 percent), and partial desensitization (≥240 mg but <4000 mg) was achieved in seven patients. Of the fully desensitized patients, all 46 who underwent a follow-up OFC after a median of eight months of maintenance therapy passed the challenge. The other three fully desensitized patients continued OIT but did not undergo an OFC. Of the seven partially desensitized patients, only three continued regular maintenance consumption, while four discontinued OIT (two patients because of daily dosing interfering with their activities and two because of food aversion). During the build-up phase, adverse reactions occurred in 4.7 percent of escalation doses administered in clinic and 2 percent of home doses, with 10 and 5 patients (16.7 and 8.3 percent) receiving treatment with epinephrine for clinic and home doses, respectively. During the maintenance phase, no serious reactions were reported, and only two patients experienced a few mild reactions. No patients in the control group tolerated sesame after a median follow-up of 26.8 months: Two (13 percent) had anaphylactic reactions to accidental exposures to sesame, and nine failed sesame oral challenge.

OTHER OIT PROTOCOLS — While single-food OIT is the most extensively studied, other approaches to OIT under investigation include OIT with multiple foods, OIT with altered allergens, and OIT combined with another therapy that, in theory, may decrease the risk of allergic reactions or improve the chance of development of tolerance.

Multifood OIT — Aeroallergen-specific immunotherapy frequently combines multiple allergens, and this multiallergen approach is under investigation for foods. A phase-I safety study of a multifood OIT was conducted in parallel with peanut OIT in subjects with peanut allergy [64]. Forty subjects reacted at the baseline double-blind, placebo-controlled food challenge (DBPCFC) to a maximum cumulative dose of 182 mg of peanut protein; of those, 25 had additional food allergies (eg, walnut, cashew, pecan, almond, hazelnut, milk, egg, and sesame) confirmed by DBPCFC. Fifteen patients received peanut OIT only. OIT was done with two foods in six participants, three foods in eight, four foods in five, and five foods in six. The protocol had three phases: the initial dose escalation day, home dosing with biweekly up-dosing, and the maintenance phase. The daily maintenance dose was 4000 mg protein of each allergen, with up to 20,000 mg as a cumulative dose for five-food OIT. Rates of reaction per OIT dose were 3.3 percent in multifood OIT and 3.7 percent in the single OIT group. Most reactions were mild, but two severe reactions requiring epinephrine occurred in each group during home maintenance dosing. This study did not include challenges while on maintenance therapy to confirm desensitization, nor did it include evaluation of sustained unresponsiveness (SU). Large and rigorous randomized trials are needed to better assess multifood OIT.

OIT with modified allergens — Approximately 60 to 80 percent of individuals with milk or egg allergy can tolerate extensively heated or baked forms of these foods. In addition, including extensively heated milk or egg in the diet may accelerate the development of tolerance. Humoral and cellular immunologic changes seen in children with a history of milk and/or egg allergy who passed oral food challenges (OFCs) to milk and/or egg in baked goods parallel the changes reported in OIT trials [65-68]. This approach, allowing ingestion of extensively heated forms if tolerated, might be conceived as similar to OIT in that the exposure may have an immunotherapeutic effect that could lead to higher thresholds of the foods in forms that are not extensively heated. However, for the 20 to 40 percent who are unable to ingest the baked forms, there are insufficient studies addressing the use of extensively heated milk/egg for escalating doses in desensitization regimens. OIT with extensively heated milk or egg is under investigation, so far with limited success. (See "Egg allergy: Management", section on 'Extensively heated (baked) egg' and "Milk allergy: Management", section on 'Extensively heated (baked) cow's milk'.)

As an example, OIT with baked milk was attempted in 14 patients who failed native milk OIT [69]. Only three patients (21 percent) achieved the full daily dose of baked milk (1.3 g baked milk protein) after 12 months of OIT, whereas eight patients developed frequent, immediate systemic reactions to baked milk OIT. The results of this study confirm prior observations from baked milk trials that patients with a more severe phenotype of milk allergy are likely to react to baked milk. In contrast, 8 of 15 children with IgE-mediated egg allergy (aged 6 to 17 years) in another study responded favorably to gradual home-based introduction of baked egg and tolerated an open OFC to one whole hard-boiled egg after 12 months [70]. These children had not previously failed standard egg OIT. In a small trial of OIT with low allergenic hydrolyzed egg (HydE) in young children, the pass rate on the final OFC to one boiled egg at six months was not significantly different between HydE versus placebo (36 versus 21 percent, respectively) [68].

OIT plus anti-IgE — Combined treatment with anti-immunoglobulin E (anti-IgE) and specific food allergen immunotherapy appears to decrease the life-threatening side effects of allergen immunotherapy and allow for more rapid desensitization. However, serious allergic reactions requiring treatment with epinephrine may still occur during desensitization and are more commonly reported to occur with OIT after discontinuation of omalizumab. In addition, treatment with omalizumab does not appear to decrease the risk of developing eosinophilic esophagitis in patients receiving OIT. Safety and feasibility studies of milk, egg, and peanut OIT, as well as multifood OIT, combined with anti-IgE have been reported. Most of the preliminary data on treatment with omalizumab prior to OIT are encouraging. Larger clinical trials underway will help clarify which patients would benefit most from this approach.

In two small, pilot studies for milk OIT and one for peanut, patients received omalizumab pretreatment prior to OIT [71-73]. These high-risk patients were able to tolerate much higher doses of allergen in much shorter periods of time compared with patients in prior studies of OIT without omalizumab. Nearly all patients tolerated rush desensitization to milk or peanut on the first day of dosing, but one patient required treatment with epinephrine for a reaction. Almost all of the patients (90 to 100 percent) also reached the maximum maintenance dose targeted and were considered desensitized. In two of the studies, all patients who were continued on daily maintenance therapy passed oral challenges 8 to 12 weeks after discontinuation of omalizumab [72,73]. However, 6 of 14 patients (43 percent) in the other study developed anaphylaxis to therapy 2.5 to 4 months after stopping omalizumab [74].

In one small trial of milk OIT plus omalizumab, adverse reactions were lower in the omalizumab group compared with placebo, but there were no significant differences in the percent of patients demonstrating desensitization (89 versus 71 percent) or SU (48 versus 36 percent) [74]. In another small trial of peanut OIT plus omalizumab, there was a significant difference in desensitization rates (79 versus 12 percent for omalizumab versus placebo, respectively), but overall reaction rates were similar in both groups [49].

Pretreatment with omalizumab combined with multifood OIT is also under investigation. In a pilot study, 25 children who had failed an initial DBPCFC at a protein dose of 100 mg or less for each included food were pretreated with omalizumab for 16 weeks and then treated with rush OIT for multiple foods [75]. Nineteen participants (76 percent) were able to complete all six steps of the initial escalation day (up to 1250 mg of combined food proteins) with minimal or no rescue therapy. All patients reached the maintenance dose of 4000 mg protein per allergen. Participants reported 401 reactions per 7530 home doses (5.3 percent); 94 percent of reactions were mild, but there was one severe reaction.

In a subsequent trial, 48 children aged 4 to 15 years with multiple food allergies (two to five foods, confirmed by failed DBPCFC at a dose of ≤500 mg of food protein) were randomly assigned 3:1 to pretreatment with omalizumab or placebo for eight weeks [76]. Both groups were then treated with multifood OIT from weeks 8 to 36. Omalizumab or placebo was continued for 16 weeks total. A greater percent of patients treated with both omalizumab and OIT demonstrated desensitization (passed 2 g of protein DBPCFCs) to at least two of their offending foods compared with those treated with OIT alone (83 versus 33 percent, odds ratio [OR] 10.0, 95% CI 1.8-58.3). Patients in the omalizumab group also had a lower percentage of OIT doses associated with any adverse events compared with placebo (median per-participant percentage of doses 27 versus 68 percent). No serious adverse events were reported.

OIT plus dupilumab — Dupilumab is a fully human monoclonal antibody directed against the receptors for interleukin (IL) 4 and IL-13, which are involved in allergic inflammation. It has demonstrated good efficacy and safety for the treatment of allergic disorders that are frequently comorbid with food allergy, including atopic dermatitis and persistent asthma, and has shown promise in eosinophilic esophagitis [77]. Dupilumab is also a potential therapeutic agent for food allergy. An ongoing large, multicenter clinical trial (NCT03682770) is evaluating efficacy and safety of dupilumab as an adjunct to peanut OIT. The primary objective is to assess whether the addition of dupilumab improves the rate desensitization at the completion of up-dosing compared with OIT alone.

OIT plus adjuvant — OIT can lead to desensitization in some patients, but the ability of OIT to induce tolerance to the food is less clear. Longer duration of therapy may be a means to induce SU, as described above (see 'Efficacy and adverse effects' above and 'Single-food OIT' above), but adding an immunostimulatory adjuvant, such as a probiotic or unmethylated CpG motifs, may be another.

The efficacy and safety of OIT using CpG-coated poly(lactic-co-glycolic acid) nanoparticles containing peanut extract (CpG/PN-NPs) was evaluated in a murine model of peanut allergy [78]. Peanut-allergic mice treated with CpG/PN-NPs, but not vehicle or other treatment components, were significantly protected from anaphylaxis to all five oral peanut challenges. CpG/PN-NP treatment did not cause anaphylactic reactions. These preclinical findings suggest that peanut OIT with CpG/PN-NPs is worth investigating in human subjects.

Improving SU to OIT by combining it with a probiotic is also under investigation. In one randomized trial, 62 children (mean age six years) with peanut allergy were randomly assigned to probiotic Lactobacillus rhamnosus CGMCC 1.3724 and peanut OIT (probiotic and peanut oral immunotherapy [PPOIT]) or placebo [79]. Desensitization and SU after two weeks of avoidance were achieved in 90 and 82 percent receiving PPOIT and 7 and 4 percent receiving placebo, respectively. In a follow-up study four years after cessation of treatment, 67 percent of patients (16 of 24) in the treatment group had continued eating peanut compared with 4 percent (1 of 24) in the placebo group [80]. Among those who underwent a DBPCFC after eight weeks of avoidance, 58 percent (7 of 12) in the treatment group had SU compared with 7 percent (1 of 15) in the placebo group. However, if one considers all enrolled in the initial trial treatment group, only 23 percent (7 of 31) achieved SU, not 58 percent, a rate similar to that seen in previously reported studies of OIT without probiotic adjuvant. In addition, there was no difference in the numbers of serious reactions between the two groups during this follow-up period (11 reactions in four patients in the PPOIT group compared with 9 reactions in six patients in the placebo group). Furthermore, there were several other significant flaws in study design (absence of blinding, no preceding DBPCFC to confirm peanut allergy prior to the start of the trial, and lack of proper controls [peanut OIT alone, probiotic alone]) that limit the conclusions that can be drawn from these results [81].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Food allergy".)

SUMMARY AND RECOMMENDATIONS

The ultimate goal of therapy for food allergy is to be able to consume the food ad libitum without symptoms or fear of a reaction. This would require induction of permanent tolerance to the food, where the allergy will not recur upon reexposure after any period of abstinence. However, achieving permanent tolerance to a food with oral immunotherapy (OIT) has proved elusive in most studies of food allergy treatments. Thus, the goal of most available treatments is to increase the amount of food persons with food allergies are able to consume before they experience symptoms (increased allergic threshold). (See 'Introduction' above and 'Goals' above and 'Tolerance versus desensitization' above and "Investigational therapies for food allergy: Immunotherapy and nonspecific therapies".)

Management of food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. OIT involves daily feeding of gradually increasing doses of the food allergen until a daily maintenance dose is reached. One of the appeals of this therapy is that much of the dosing can be done at home. (See 'Introduction' above and 'General protocol' above and "Management of food allergy: Avoidance".)

A majority of patients treated with OIT are at least partially desensitized (have an increased threshold for a reaction). However, this desensitization does not translate into overall decreased allergic reactions in the real-world setting, when reactions to the treatment product are included. In addition, only a minority of patients treated with OIT achieve sustained unresponsiveness (SU) that is independent of regular food intake and is maintained even if the food is eliminated from the diet for long periods of time. Thus, for most allergens, it appears that OIT would need to be continued indefinitely to maintain a protective effect. (See 'Efficacy and adverse effects' above.)

Allergic reactions to OIT are common, particularly during the build-up phase of dosing, and occur at higher rates overall in patients on OIT than those avoiding the food. Oral and gastrointestinal symptoms are the most common, followed by lower respiratory symptoms (eg, wheeze). Anaphylaxis is uncommon but occurs more frequently in patients on OIT than in patients who avoid the food. Systemic reactions may occur at previously tolerated doses, particularly in the setting of exercise or viral illness. Some patients have been diagnosed with eosinophilic esophagitis after undergoing OIT. (See 'Efficacy and adverse effects' above.)

Most studies of OIT have involved treatment with only a single food. However, many children have multiple food allergies. Thus, researchers are beginning to explore OIT with multiple food allergens. Additional approaches include OIT with modified food allergens and OIT combined with immunomodulatory biologic agents such as anti-immunoglobulin E (anti-IgE) or immunostimulatory adjuvant, such as a probiotic or unmethylated CpG motifs. (See 'Single-food OIT' above and 'Other OIT protocols' above.)

While peanut OIT is effective at increasing supervised in-clinic food challenge thresholds (ie, desensitization), it increases the risk of anaphylaxis, other allergic reactions, and need for epinephrine. In addition, there are considerable burdens and costs associated with peanut OIT, including clinic visits for supervised dose escalations, an indefinite period of treatment, the continued need to avoid peanut in the diet, costs of the standardized peanut OIT powder, dosing restrictions (eg, timing, type of food it can be ingested with), and the need to avoid potential triggers of an allergic reaction (eg, hot showers). Many patients are unlikely to be good candidates for peanut OIT, either because they already have a threshold that is high enough to make accidental ingestion reactions unlikely or because the adverse effect profile and daily commitments required for therapy outweigh any potential benefit of increasing the reaction threshold. (See 'Peanut' above and 'General protocol' above and 'Minimizing risk of systemic reactions' above.)

Despite the increased risk of anaphylaxis and other adverse effects, some patients may be motivated to try OIT, rather than continue avoidance alone, in the hope that it may alleviate some of the anxiety and fear of experiencing a severe allergic reaction in the event of accidental peanut ingestion. For such patients, it is important to provide accurate information on the anticipated effects of OIT, particularly that it increases rather than decreases risk of anaphylaxis and that, based upon the available data, it does not appear to improve quality of life (QOL). If OIT is undertaken, appropriate safety precautions are critical.

The limited clinical trial data on other single-food OIT (eg, milk, egg, wheat, sesame) suggest these therapies may achieve desensitization, but they have not been shown to reduce the risk of anaphylaxis and, in fact, may increase the risk. In addition, there are no approved preparations of these allergens. (See 'Cow's milk' above and 'Hen's egg' above and 'Wheat' above and 'Sesame' above.)

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  81. http://allergen-nce.ca/wp-content/uploads/Chu-Jordana-Waserman-OIT-statement.pdf.
Topic 113421 Version 19.0

References

1 : Allergen-Specific Immunotherapies for Food Allergy.

2 : Food allergy: a practice parameter update-2014.

3 : EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy.

4 : Japanese guidelines for food allergy 2017.

5 : Oral tolerance: lessons on treatment of food allergy.

6 : Immunotherapy in the treatment of food allergy: focus on oral tolerance.

7 : Component-resolved analysis of IgA, IgE, and IgG4 during egg OIT identifies markers associated with sustained unresponsiveness.

8 : Oral immunotherapy for treatment of egg allergy in children.

9 : Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3).

10 : MIP-1α, MCP-1, and desensitization in anaphylaxis from cow's milk.

11 : Evidence of pathway-specific basophil anergy induced by peanut oral immunotherapy in peanut-allergic children.

12 : Food allergy.

13 : Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management.

14 : Psychosocial Mediators of Change and Patient Selection Factors in Oral Immunotherapy Trials.

15 : Open-label maintenance after milk oral immunotherapy for IgE-mediated cow's milk allergy.

16 : Adverse reactions during peanut oral immunotherapy home dosing.

17 : Safety of a peanut oral immunotherapy protocol in children with peanut allergy.

18 : Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction.

19 : Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety.

20 : Oral immunotherapy in children with IgE-mediated wheat allergy: outcome and molecular changes.

21 : Wheat oral immunotherapy for wheat-induced anaphylaxis.

22 : Evaluation of a new protocol for wheat desensitization in patients with wheat-induced anaphylaxis.

23 : A Safe and Effective Method for Wheat Oral Immunotherapy.

24 : Oral Immunotherapy With Partially Hydrolyzed Wheat-Based Cereals: A Pilot Study.

25 : Multicenter, randomized, double-blind, placebo-controlled clinical trial of vital wheat gluten oral immunotherapy.

26 : Efficacy and Safety of Sesame Oral Immunotherapy-A Real-World, Single-Center Study.

27 : Oral specific hyposensitization in the management of patients allergic to food.

28 : Food allergy in children: results of a standardized protocol for oral desensitization.

29 : Oral hyposensitization with celery juice.

30 : Severity and threshold of peanut reactivity during hospital-based open oral food challenges: An international multicenter survey.

31 : Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective.

32 : A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.

33 : Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial.

34 : Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial.

35 : AR101 Oral Immunotherapy for Peanut Allergy.

36 : Feasibility of desensitizing children highly allergic to peanut by high-dose oral immunotherapy.

37 : Efficacy and safety of oral immunotherapy in children aged 1-3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-controlled study.

38 : Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy.

39 : Clinical efficacy and immune regulation with peanut oral immunotherapy.

40 : Allergen-specific oral immunotherapy for peanut allergy.

41 : Oral tolerance, food allergy, and immunotherapy: implications for future treatment.

42 : Oral peanut immunotherapy in children with peanut anaphylaxis.

43 : Efficacy and safety of high-dose peanut oral immunotherapy with factors predicting outcome.

44 : Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study.

45 : Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study.

46 : Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study.

47 : Five-year follow-up of early intervention peanut oral immunotherapy.

48 : Oral immunotherapy for peanut allergy: multipractice experience with epinephrine-treated reactions.

49 : Omalizumab facilitates rapid oral desensitization for peanut allergy.

50 : Oral immunotherapy for IgE-mediated cow's milk allergy: a systematic review and meta-analysis.

51 : Oral immunotherapy for milk allergy.

52 : Life-threatening asthma reaction caused by desensitization to milk.

53 : Possible eosinophilic esophagitis induced by milk oral immunotherapy.

54 : Primary eosinophilic gastrointestinal disorders in children who have received food oral immunotherapy.

55 : Long-term follow-up of oral immunotherapy for cow's milk allergy.

56 : Oral and sublingual immunotherapy for egg allergy.

57 : Oral and sublingual immunotherapy for egg allergy.

58 : Long-term treatment with egg oral immunotherapy enhances sustained unresponsiveness that persists after cessation of therapy.

59 : A 5-year summary of real-life dietary egg consumption after completion of a 4-year egg powder oral immunotherapy (eOIT) protocol.

60 : Egg oral immunotherapy in nonanaphylactic children with egg allergy.

61 : Egg oral immunotherapy in non-anaphylactic children with egg allergy: follow-up.

62 : Individualized IgE-based dosing of egg oral immunotherapy and the development of tolerance.

63 : Oral rush desensitization to egg: efficacy and safety.

64 : Safety and feasibility of oral immunotherapy to multiple allergens for food allergy.

65 : Tolerance to extensively heated milk in children with cow's milk allergy.

66 : Immunologic changes in children with egg allergy ingesting extensively heated egg.

67 : Association of allergen-specific regulatory T cells with the onset of clinical tolerance to milk protein.

68 : Oral immunotherapy with low allergenic hydrolysed egg in egg allergic children.

69 : Efficacy of baked milk oral immunotherapy in baked milk-reactive allergic patients.

70 : Home-Based Oral Immunotherapy With a Baked Egg Protocol.

71 : Rapid oral desensitization in combination with omalizumab therapy in patients with cow's milk allergy.

72 : A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanut-allergic patients.

73 : Anti-IgE-assisted desensitization to egg and cow's milk in patients refractory to conventional oral immunotherapy.

74 : A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy.

75 : Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab.

76 : Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial

77 : Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis.

78 : Investigation of peanut oral immunotherapy with CpG/peanut nanoparticles in a murine model of peanut allergy.

79 : Administration of a probiotic with peanut oral immunotherapy: A randomized trial.

80 : Long-term clinical and immunological effects of probiotic and peanut oral immunotherapy after treatment cessation: 4-year follow-up of a randomised, double-blind, placebo-controlled trial