Desensitization and Remission after Peanut Sublingual Immunotherapy in 1- to 4-year-old Peanut-Allergic Children: a Randomized, Placebo-Controlled Trial

Abstract

BACKGROUND:

Prior studies of peanut sublingual immunotherapy (SLIT) have suggested a potential advantage with younger age of initiating treatment.

OBJECTIVE:

To study the safety and efficacy of SLIT for peanut allergy in 1–4 year-old children.

METHODS:

Peanut-allergic 1–4 year-old children were randomized to receive 4 mg peanut SLIT versus placebo. Desensitization was assessed by double-blind, placebo-controlled food challenge (DBPCFC) after 36 months of treatment. Participants desensitized to at least 443 mg peanut protein discontinued therapy for three months and then underwent DBPCFC to assess for remission. Biomarkers were measured at baseline and longitudinally during treatment.

RESULTS:

Fifty participants (25 peanut SLIT, 25 placebo) with a median age of 2.4 years were enrolled across two sites. The primary endpoint of desensitization was met with actively treated versus placebo participants having a significantly greater median cumulative tolerated dose (4443 mg versus 143 mg), higher likelihood of passing the month 36 DBPCFC (60% versus 0%), and higher likelihood of demonstrating remission (48% versus 0%). The highest rate of desensitization and remission was seen in 1–2 year-old, followed by 2–3 year-old, and 3–4 year-old participants. Longitudinal changes in peanut skin prick testing, peanut-specific IgG4, and peanut-specific IgG4/IgE ratio were seen in peanut SLIT but not placebo participants. Oropharyngeal itching was more commonly reported by peanut SLIT than placebo participants. Skin, gastrointestinal, upper respiratory, lower respiratory, and multi-system adverse events were similar between treatment groups.

CONCLUSION:

Peanut SLIT safely induces desensitization and remission in 1–4 year-old children with improved outcomes seen with younger age of initiation.

CLINICAL TRIAL REGISTRATION:

The study was registered at clinicaltrials.gov with registration # NCT02304991.

CAPSULE SUMMARY:

Peanut SLIT induced greater desensitization and 3-month remission compared to placebo in 1–4 year-old children. Oropharyngeal itching was the most commonly reported adverse event with peanut SLIT.

Graphical Abstract

INTRODUCTION

Peanut allergy typically develops early in life, affecting approximately one to two percent of children in Western nations. Once established, peanut allergy is rarely outgrown and is the food allergy most commonly linked to fatal food-induced anaphylaxis.^1–3 While peanut-induced allergic reactions are generally infrequent, the vigilance required to avoid ingestion of peanut, coupled with the anxiety and social isolation commonly associated with a life-threatening food allergy create a significant burden for patients and their families. The impact of this burden often leads to a decreased quality of life.^{1, 4, 5}

Oral immunotherapy (OIT) has been the best-studied treatment for peanut allergy and the ability of peanut OIT to induce desensitization has been shown across multiple studies of peanut-allergic children and adolescents.^6–8 However, side effects from peanut OIT affect most patients on therapy. While most treatment side effects are mild to moderate in severity, severe reactions do occur and there remains a critical need to develop treatment modalities with more manageable side effect profiles.

Sublingual immunotherapy (SLIT) is an approach to administering allergen that takes advantage of the unique immunologic environment of the oral mucosa⁹, allowing for antigen delivery and uptake in a place with a relative paucity of effector cells compared to the skin and other mucosal sites.¹⁰ This allows for a potentially safer route to administer allergen for desensitization compared to the orally ingested and subcutaneous routes. Our group has shown successful desensitization with peanut SLIT after 12 months of therapy when compared to placebo.¹¹ When treatment was extended to a three to five year course, peanut SLIT remained safe with the most common side effect consisting of transient oral itching.¹² Furthermore, the potential for a sustained treatment effect lasting up to four weeks was seen after discontinuing therapy.¹²

Additional studies have supported the safety and efficacy of peanut SLIT;¹³⁻¹⁵ however, the magnitude of desensitization across published studies has varied. Comparison of the cohorts from these studies has suggested the possibility of stronger desensitization associated with younger age at treatment. To investigate the safety and efficacy of peanut SLIT among young children, we designed a 36-month, multi-center, double-blind, randomized, placebo-controlled study of peanut SLIT in peanut-allergic children one to four years of age.

METHODS

STUDY DESIGN AND PARTICIPANT SELECTION

This two-center, randomized, double-blind study was conducted at two large academic sites, the University of North Carolina (UNC) and the University of Texas Southwestern (UTSW). The study was registered on clinicaltrials.gov (NCT02304991) and conducted under an Investigational New Drug application to the United States Food and Drug Administration and was monitored by an independent data and safety monitoring board. Study protocol and consent forms were approved by the Institutional Review Boards at each clinical site. Written informed consent was obtained from parents or guardians.

Peanut-allergic participants ages one to four years inclusive of any sex, race, and ethnicity were enrolled. Participants with a convincing clinical history of peanut allergy required a peanut-specific IgE (pn-sIgE) ≥ 0.35 kU_A/L and a positive peanut skin prick test (SPT) (wheal size at least 3 mm greater than the negative control). Participants without a history of peanut ingestion required a larger pn-sIgE ≥ 5 kU_A/L along with a positive peanut SPT. All participants required a positive reaction during a double-blind, placebo-controlled food challenge (DBPCFC) to 1000 mg peanut protein to be randomized. Key exclusion criteria included a history of severe anaphylaxis to peanut defined as hypoxia, hypotension, or neurologic compromise; eosinophilic or other inflammatory gastrointestinal disease; and severe asthma (2007 NHLBI Criteria Steps 5 or 6).¹⁶ Complete inclusion and exclusion criteria are listed in Supplemental Table 1.

RANDOMIZATION AND BLINDING

Participants were randomly assigned by a centralized computer algorithm to receive study drug with either peanut SLIT or placebo SLIT (in a ratio of 1:1). Patients and study staff were blinded through completion of the final DBPCFC. The locked randomization list was maintained by a third-party data management team (Advance Research Associates, Santa Clara, CA) until study completion. Oat flour was used as a placebo during DBPCFC and the order of peanut and placebo portions of the DBPCFC was determined by coin flip by unblinded site research kitchen staff.

STUDY DRUG

The peanut SLIT study drug was comprised of liquid peanut extract (5000 μg/ml peanut protein) manufactured by and purchased from Greer Laboratories (Lenoir, NC). The placebo SLIT was comprised of pure glycerinated saline solution with caramel coloring to match color. Glycerinated saline was used to create study drug dilutions by trained staff at the UNC Food Allergy Initiative (Chapel Hill, NC). Peanut SLIT and placebo SLIT were aliquoted into opaque vials with pumps dispensing 50 μl of study drug per actuation. SLIT vials were labeled and provided to the site-specific investigational drug pharmacist, followed by distribution to study staff, and final dispensation to participants.

SLIT DOSING PROTOCOL

Study drug dosing started under observation at the clinical sites with one pump of SLIT from a 1:100 dilution of peanut (2.5 μg peanut protein) or placebo. The dose was held under the tongue for two minutes and then swallowed. If tolerated, parents were instructed to administer the same dose at home once daily. Home dose escalations alternated with four monthly in-clinic observed dose escalations according to the dosing protocol (Supplemental Table 2). Dose escalations continued until the 4 mg maintenance dose was achieved. While on maintenance dosing, participants returned to the research clinic every six months for follow-up. Parents were instructed to avoid peanut in the participant’s diet throughout the study.

DBPCFC

DBPCFC were conducted in research clinics by a study nurse with oversight by site investigators. At entry, all participants underwent a 1000 mg cumulative challenge consisting of six doses administered 10 to 20 minutes apart as follows: 3, 10, 30, 100, 300, 557 mg peanut protein. For the placebo portion of the DBPCFCs, oat flour was administered in identical doses by weight. At month 36, the DBPCFC was conducted to a cumulative dose of 4443 mg and administered in seven doses as follows: 3, 10, 30, 100, 300, 1000, 3000 mg. Participants with a CTD of at least 443 mg at the month 36 DBPCFC were instructed to stop the study drug and continue peanut avoidance for three months. A final month 39 DBPCFC was then conducted to assess for remission. The DBPCFC was discontinued if one major or two minor stopping criteria were observed (Supplemental Table 3). The DBPCFC was scored as a pass if the participant ingested all doses and completed two hours of observation without meeting stopping criteria.

IMMUNE MARKERS

SPT and blood draws for immunologic studies were performed at screening and at months 12, 24, 36, and 39. SPT was performed with a standard peanut extract (1:20 wt/vol, Greer Laboratories, Lenoir, NC), a histamine positive control, and a saline negative control with results reported as the difference in peanut wheal size compared to the negative control. Serum pn-sIgE and peanut-specific IgG4 (pn-sIgG4) antibody levels were measured with the use of the ImmunoCAP 100 (Thermo Fisher Scientific, Waltham, MA). Ratios of pn-sIgG4 to pn-sIgE were calculated using a conversion factor of 2.42 μg/L = 1 kU_A/L for pn-sIgE as previously described.¹²

OUTCOMES

The primary endpoint of the study was desensitization defined as a statistically significant difference in the CTD during DBPCFC at month 36 for peanut SLIT participants versus placebo participants. CTD was represented by a challenge score for calculation of the hazard of failure at each challenge dose across the DBPCFC as described by Sampson, et al in the PRACTALL food challenge consensus report.¹⁷ Additional analyses of the primary endpoint included the median CTD after treatment and the proportion of participants passing the month 36 DBPCFC after treatment. Secondary endpoints included the proportion of participants achieving remission defined as passing the month 39 DBPCFC after the avoidance period and longitudinal changes in immune markers. For post-hoc analysis of the effect of age on study outcomes, baseline age was categorized as 1–2 years, 2–3 years, and 3–4 years.

SAFETY REPORTING

Parents documented daily dosing of the study drug and any symptoms within two hours of home dosing through diary logs. Symptoms reported within two hours of dosing were generally considered possibly related to study drug unless a clear alternative cause was identified by the investigator. The severity of allergic reactions during study drug dosing or DBPCFC was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version four (NCI-CTCAE) with scores ranging from one (transient or mild discomfort) to five (death) (Supplemental Table 4).

STATISTICAL ANALYSIS

We calculated the sample size considering a 1:1 randomization, a two-sided p-value of 0.05, a 20% pass rate on placebo, and assuming a 20% drop out rate. A sample size of 50 participants was calculated to achieve 90% power to detect a pass rate of 80% or higher for peanut SLIT participants. All participants initiating study drug dosing comprised the intent to treat (ITT) population. Participants who completed the DBPCFC at month 36 comprised the per protocol (PP) population. For the primary endpoint, conditional logistic regression was utilized to estimate the hazard of reacting at each DBPCFC dose for peanut SLIT participants compared to placebo participants at month 36 in a method adapted from Sampson, et al in the PRACTALL food challenge consensus report.¹⁷ T-tests were used to assess pass rates during DBPCFC at month 36 and month 39 and to compare the median CTD at month 36 between peanut SLIT and placebo participants. Longitudinal changes in SPT and peanut-specific immunoglobulins were assessed in the PP population using a mixed effects model with Dunnett’s test for multiple comparisons. Generalized estimating equations that accounted for within person correlation and Fisher’s exact test were used to compare overall and per person rates of side effects during peanut SLIT versus placebo dosing, respectively. All analyses were done with GraphPad Prism 9 (GraphPad Software, Boston, MA) and STATA 17 (StataCorp LLC, College Station, TX).

RESULTS

STUDY PARTICIPANTS

A total of 50 participants (40 at UNC, 10 at UTSW) were enrolled. Participants were randomized 1:1 with 25 receiving peanut SLIT and 25 receiving placebo, representing the ITT population. Baseline characteristics of the cohort are shown in Table 1. The mean age of participants was 2.4 years and 44% were female and 88% White. The majority of participants had concomitant atopic dermatitis (80%) and additional food allergies (74%). Median CTD at baseline for peanut SLIT participants was 143 mg (IQR 43–143) and for placebo participants was 43 mg (IQR 43–143).

Table 1:

Baseline characteristics

	Peanut SLIT	Placebo	All
Total participants, n	25	25	50
Site, n (%)
UNC	20 (80%)	20 (80%)	40 (80%)
UTSW	5 (20%)	5 (20%)	10 (20%)
Participants by age, n (%)
Age 1–2 years	12 (48%)	11 (44%)	23 (46%)
Age 2–3 years	6 (24%)	5 (20%)	11 (22%)
Age 3–4 years	7 (28%)	9 (36%)	16 (32%)
Age, median (IQR)	2.2 years (1.5–3.5)	2.4 years (1.6–3.4)	2.2 years (1.6–3.5)
Sex, n (%)
Male	12 (48%)	16 (64%)	28 (56%)
Female	13 (52%)	9 (36%)	22 (44%)
Race, n (%)
White	21 (84%)	23 (92%)	44 (88%)
Black	0	2 (8%)	2 (4%)
Asian	1 (4%)	0	1 (2%)
American Indian	1 (4%)	0	1 (2%)
Mixed race	2 (8%)	0	2 (4%)
Comorbid atopic diseases, n (%)
Asthma	7 (28%)	6 (24%)	13 (26%)
Atopic dermatitis	21 (84%)	19 (76%)	40 (80%)
Allergic rhinitis	7 (28%)	12 (48%)	19 (38%)
Other food allergies	19 (76%)	18 (72%)	37 (74%)
Baseline Pn-SPT, median (IQR)	10.0 mm (8.0–14.0)	11.5 mm (8.0–13.0)	10.3 mm (8.0–13.8)
Baseline Pn-sIgE, median (IQR)	4.3 kUA/L (1.7–13.7)	19.5 kUA/L (10.4–76.0)	12.9 kUA/L (3.6–42.3)
Baseline Pn-sIgG4, median (IQR)	0.2 mg/L (0.1–0.4)	0.3 mg/L (0.1–1.1)	0.3 mg/L (0.1–0.6)
Baseline DBPCFC, median (IQR)	143 mg (43–143)	43 mg (43–143)	43 mg (43–143)

PARTICIPANT FLOW

Participant flow is shown in Figure 1. Nineteen of 25 (76%) peanut SLIT participants and 17 of 25 (68%) placebo participants completed the month 36 DBPCFC representing the PP population. Sixteen (64%) peanut SLIT participants and four (16%) placebo participants completed the month 39 DBPCFC. Six peanut SLIT participants withdrew consent during SLIT dosing, one participant withdrew consent during the avoidance phase, and two participants did not qualify for the month 39 DBPCFC per the protocol. Eight placebo participants withdrew consent during SLIT dosing, 2 participants withdrew consent during the avoidance phase, and eleven participants did not qualify for the month 39 DBPCFC per the protocol.

Figure 1:

Participant flow diagram

ASSESSMENT OF CLINICAL RESPONSES

Month 36 Desensitization and Month 39 Remission Outcomes

The primary endpoint of the study was met by comparison of hazard of failure across food challenge doses (p < 0.001) and by comparison of the median CTD for peanut SLIT participants (4443 mg, dose 7) versus for placebo participants (143 mg, dose 4) at the 36-month DBPCFC (p < 0.0001) (Supplemental Figure 1). Fifteen peanut SLIT participants (ITT: 60%, PP: 78.9%) versus zero placebo participants passed the month 36 DBPCFC by ingesting the full 4443 mg of peanut protein without dose-limiting symptoms (p < 0.0001) (Figure 2A). Twelve peanut SLIT participants (ITT: 48%, PP: 63%) versus zero placebo participants went on to pass the month 39 DBPCFC demonstrating remission (p = 0.0005) (Figure 2B).

Figure 2A-B:

Percentage of participants passing the peanut oral food challenge during the (A) month 36 desensitization DBPCFC and (B) month 39 remission DBPCFC. ITT group includes 25 participants per arm. Per protocol group includes 19 peanut SLIT and 17 placebo participants. ***p = 0.005, ****p < 0.0001.

Considering changes compared to baseline, the median CTD for peanut SLIT participants increased from 143 mg at baseline to 4443 mg at month 36 (p < 0.0001). The median CTD for placebo participants increased from 43 mg at baseline to 143 mg at month 36 (p = 0.024). All peanut SLIT participants increased from baseline while 13 placebo participants increased and 4 placebo participants decreased from baseline.

The desensitization and remission outcomes respectively were compared across baseline pn-sIgE, peanut SPT, CTD during DBPCFC, and age at enrollment. Baseline pn-sIgE (p = 0.002) and age at enrollment (p=0.014) were significantly lower in participants achieving desensitization compared to those failing desensitization while no difference was seen in baseline peanut SPT and DBPCFC (Supplemental figure 3). Baseline pn-sIgE (p = 0.013) was significantly lower in participants achieving remission while no difference was seen in baseline peanut SPT, DBPCFC, or age at enrollment (Supplemental figure 4).

Immunologic Changes

When compared to baseline, the median peanut SPT wheal size for peanut SLIT participants decreased significantly at month 12 (p = 0.0012), at month 24 (p = 0.0003), and at month 36 (p < 0.0001). SPT for placebo participants did not change significantly over the course of treatment (Figure 3A).

Figure 3A-D:

Longitudinal analysis of (A) peanut skin prick test, (B) peanut-specific IgE, (C) peanut-specific IgG4, and (D) peanut-specific IgG4/IgE ratio in the per protocol group. Red lines depict the median values. Values at all time points were compared to baseline. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

The median pn-sIgE for peanut SLIT participants decreased when compared to baseline but did not reach statistical significance at month 12 (p = 0.334), at month 24 (p = 0.074), or at month 36 (p = 0.188) (Figure 3B). Of note, the pn-sIgE for placebo participants was increased significantly at month 36 (p = 0.043). The median pn-sIgG4 for peanut SLIT participants increased significantly compared to baseline at month 12 (p = 0.030), at month 24 (p = 0.003), and at month 36 (p = 0.004) (Figure 3C). The corresponding median pn-sIgG4/IgE ratio for peanut SLIT participants was increased at month 12 (p = 0.153) and reached statistical significance at month 24 (p = 0.029) and at month 36 (p = 0.017) (Figure 3D). Pn-sIgG4, and pn-sIgG4/IgE ratio did not change significantly over the course of treatment for placebo participants. Comparing treatment groups at month 36, the median peanut SPT for peanut SLIT versus placebo participants was 3.3 mm versus 12.0 (p < 0.0001), pn-sIgE was 1.0 kUA/L versus 71.8 kUA/L (p = 0.002), and pn-sIgG4/IgE was 804.5 versus 10.6 (p = 0.013). Pn-sIgG4 was not significantly different (p = 0.37) across treatment groups at month 36 (supplemental figure 5).

AGE-RELATED OUTCOMES

DBPCFC and immunological changes were further analyzed with respect to baseline age of participants. Among peanut SLIT participants, baseline age and month 36 desensitization DBPCFC outcomes were negatively correlated with a DBPCFC decrease of 965 mg for each year of increasing age (r² = 0.29, p = 0.018) (Figure 4A). The highest desensitization rate was observed for 1–2 year-old participants (ITT: 75%, PP: 100%) with decreasing rates for 2–3 year-old (ITT: 50%, PP: 75%) and 3–4 year-old participants (ITT: 43%, PP: 50%) (Figure 4B). The percentage of participants achieving remission was also highest for 1–2 year-old participants (ITT: 58%, PP: 78%) and decreased for 2–3 year-old (ITT: 33%, PP: 50%) and 3–4 year-old participants (ITT: 43%, PP: 50%) (Figure 4C).

Figure 4A-C:

Analysis of (A-B) desensitization and (C) remission oral food challenge outcomes by age. Red lines depict the median values. ITT group includes age 1–2 years: 12 participants; 2–3 years: 6 participants; 3–4 years: 7 participants. Per protocol group includes age 1–2 years: 9 participants; 2–3 years: 4 participants; 3–4 years: 6 participants.

Clear age-related trends in peanut SPT, pn-sIgE, pn-sIgG4, or pn-sIgG4/IgE ratio were not seen for peanut SLIT or placebo participants (Supplemental Figure 2A-D).

SAFETY AND COMPLIANCE

Compliance with SLIT dosing and parent-reported side effects are shown in Table 2. Significantly more doses were missed by peanut SLIT participants (7.9%) when compared to placebo participants (5.6%, p < 0.0001). All peanut SLIT and placebo participants reported at least one adverse event considered possibly to study drug dosing over the course of the study. Eighty percent of peanut SLIT participants reported oropharyngeal itching after dosing compared to 28% of placebo participants (p = 0.0005). The percentage of participants reporting skin, gastrointestinal, upper respiratory, lower respiratory, or multi-system symptoms was not significantly different between peanut SLIT and placebo participants. Although not significantly different, more placebo participants reported multi-system dosing symptoms than peanut SLIT participants (5 versus 2). No symptoms were treated with epinephrine and the percentage of participants treating dosing reactions with antihistamines and albuterol was not significantly different between peanut SLIT and placebo participants. One serious adverse event was reported in a placebo participant that was unrelated to study drug.

Table 2:

Dosing compliance and adverse events reported within 2 hours of dosing and considered possibly related to dosing.

	Peanut SLIT (n = 25)	Placebo (n = 25)
Total dosing days	23,032	24,134
Missed doses, n (%)*	1,822 (7.9%)	1,346 (5.6%)
Total doses taken, n (%)	21,210 (92.1%)	22,788 (94.4%)
Any dosing symptoms, n (% doses taken)	1,069 (5.0%)	369 (1.6%)
Local oropharyngeal	597 (2.8%)	49 (0.2%)
Skin	242 (1.1%)	154 (0.7%)
Gastrointestinal	39 (0.2%)	21 (0.1%)
Upper respiratory	9 (<0.1%)	84 (0.4%)
Lower respiratory	43 (0.2%)	70 (0.3%)
Multi-system	4 (<0.1%)@	9 (<0.1%)#
Treatment administered, n
Epinephrine	0	0
Antihistamine	39	95
Albuterol	21	61
Any dosing symptoms, participants	25 (100%)	25 (100%)
Local oropharyngeal*	20 (80%)	7 (28%)
Skin	20 (80%)	17 (68%)
Gastrointestinal	11 (44%)	8 (32%)
Upper respiratory	6 (24%)	6 (24%)
Lower respiratory	6 (24%)	4 (16%)
Multi-system	2 (8%)	5 (20%)
Treatment administered, participants
Epinephrine	0	0
Antihistamine	14 (56%)	9 (36%)
Albuterol	3 (12%)	2 (8%)

^@2 episodes involved oral itch and belly pain, 1 episode involved nasal congestion and belly pain, 1 episode involved rhinorrhea, throat clearing and cough.

^#1 episode involved mouth itch and cough, 1 episode involved hives and vomit, 4 episodes involved eczema and cough/wheeze, 3 episodes involved sneezing and cough.

^*Significant differences between treatment groups.

Considering symptoms attributed to individual doses, symptoms were reported with 5.0% of peanut SLIT doses versus 1.6% of placebo doses. Overall, the frequency of oropharyngeal, skin, gastrointestinal, upper respiratory, and lower respiratory symptoms attributed to peanut SLIT doses versus placebo doses were not statistically significant. Multi-system reactions were reported after four peanut SLIT versus nine placebo doses (p = 0.27). The peanut SLIT reactions were comprised of two episodes of oral itch and belly pain, one episode of nasal congestion and belly pain, and one episode of rhinorrhea, throat clearing, and cough. The frequency of doses resulting in treatment with antihistamines or albuterol was not significantly different between peanut SLIT and placebo doses.

Seven peanut SLIT participants versus ten placebo participants discontinued the study (Supplemental Table 5). One peanut SLIT participant declined to undergo the month 36 DBPCFC and another participant declined the avoidance phase. The remaining five peanut SLIT participants withdrew consent unrelated to dosing adverse events. Three of these five participants reported no symptoms with peanut SLIT dosing, one participant reported diarrhea on two occasions, and one participant reported rash on two occasions. Two placebo participants withdrew consent to pursue peanut OIT with their local allergists with both participants having experienced allergic reactions after accidental ingestions of peanut while participating in the study.

DISCUSSION

This is the first randomized, controlled trial to investigate the efficacy and feasibility of peanut SLIT in 1–4 year-old peanut-allergic children. Using a rigorous three-year, double-blind, placebo-controlled design, we demonstrate for the first time clinically significant desensitization with peanut SLIT in this young age group. We assessed the effect of 36 months of peanut SLIT treatment on desensitization using three methods; calculation of hazard ratio as described by PRACTALL¹⁷, the median amount of peanut protein tolerated during DBPCFC, and the proportion of participants passing the 4443 mg DBPCFC. Across all analyses, the efficacy of peanut SLIT was clearly demonstrated. Furthermore, we found a clinically and statistically significant difference in three-month remission between treatment groups, with 48% of peanut SLIT participants demonstrating remission compared to no placebo participants.

The IMPACT study investigated peanut OIT in 1–4 year-old peanut-allergic children, representing the closest comparison to our study published to date.¹⁸ Using a 2000 mg orally ingested dose, IMPACT demonstrated strong desensitization with 71% passing a DBPCFC after 30 months of treatment. With a 4 mg maintenance dose administered sublingually, we show comparable desensitization with a 60% pass rate during the month 36 DBPCFC. After six months of peanut avoidance, remission was shown in 21% of peanut OIT participants in the IMPACT study. Our study demonstrated three-month remission in 48% of peanut SLIT participants representing the longest period of SLIT avoidance assessed to date.

One of the presumed strengths of the SLIT approach when compared to OIT has been its overall safety and ease of administration. In our study approximately 92% of peanut SLIT doses were successfully administered. Similar to studies of environmental allergen SLIT¹⁹, oropharyngeal itch symptoms were reported after peanut SLIT, however, these symptoms were self-limited and resolved spontaneously without leading to more significant reactions. The rates of skin, gastrointestinal, respiratory, and multi-system reactions were not significantly different among peanut SLIT participants versus placebo participants in this study. In comparison, approximately 75% of peanut OIT treated participants in IMPACT reported gastrointestinal and respiratory symptoms. Multi-system reactions were not directly reported in IMPACT, however, 21 peanut OIT participants (34%) used epinephrine to treat symptoms during OIT dosing and ultimately seven of these 21 participants discontinued the study. In contrast, two peanut SLIT participants (8%) reported four episodes of multi-system reactions involving combinations of oral itch, nasal congestion, belly pain, post-nasal drip, and throat clearing. None of these four episodes required epinephrine and no peanut SLIT participants discontinued the study due to dosing symptoms. Furthermore, multi-system reactions were more commonly reported among placebo-treated participants suggesting that these symptoms may more likely be related to concomitant atopic disease or infections than study drug in this preschool age cohort. Taken together, these data show that peanut SLIT is very safe and supports a superior safety profile compared to peanut OIT.

The immune systems of younger children have been thought to be more pliable and perhaps more conducive to the induction of tolerance.²⁰ Peanut SPT, pn-sIgG4, and pn-sIgG4/IgE ratio changed significantly after peanut SLIT supporting immune modulation corresponding to the clinical findings of desensitization and remission. Pn-sIgE also decreased during peanut SLIT although these changes did not reach statistical significance. Interestingly, pn-sIgE was increased in the placebo group by the end of the study, a trend also seen in the IMPACT study.¹⁸ In the IMPACT study, a post-hoc analysis found a higher likelihood of achieving remission among younger children (1–2 years: 71%; 2–3 years: 35%; 3–4 years: 9%), but there were few subjects in the youngest 1–2 year-old age group, limiting the inferences that could be made.¹⁸ In contrast, nearly 50% of participants in our study initiated therapy between the ages of one and two years. As in IMPACT, we found the highest rates of desensitization in 1–2 year-old participants which decreased with increasing age (1–2 years: 75%; 2–3 years: 50%; 3–4 years: 43%). Similarly, remission was highest in this youngest group and also decreased with increasing age (1–2 years: 58%; 2–3 years: 33%; 3–4 years: 43%). Age-related trends were not seen for SPT or immunoglobulins, however the improved clinical efficacy with younger age and increasing pn-sIgE while on placebo suggests that early intervention may be important to redirect the otherwise upward trend of the allergic response in these young children.

A key strength of our study was its rigorous 1:1 randomization for 36 months. Over this period, no placebo participants naturally outgrew their peanut allergy and instead a significant increase in pn-sIgE was demonstrated. Limitations of the study included its relatively small sample size and a higher than expected rate of participant discontinuations. We were still able to show statistically significant clinical efficacy with peanut SLIT across multiple analyses of the primary outcome and using a conservative ITT analysis, the primary clinical outcome remained significant. However, conclusions drawn from the secondary outcomes including remission are limited by the lower number of participants. It was reassuring that the discontinuations did not appear to be related to dosing safety as more placebo participants discontinued than peanut SLIT participants and no peanut SLIT participants cited dosing symptoms as a reason for withdrawal. An additional limitation was a difference in baseline male:female ratio, peanut SPT, pn-sIgE, and DBPCFC at baseline between peanut SLIT and placebo participants. Despite a lower baseline pn-sIgE in peanut SLIT participants, the median SPT of 10 mm was greater than the 95% predictive level for peanut allergy²¹, and the median 143 mg SCD at baseline DBPCFC was in agreement with the entry criteria of the phase 3 PALISADES trial,⁸ supporting enrollment of an allergic population. The larger SPT, pn-sIgE, and lower DBPCFC in the placebo group may have accounted for the finding of no responders in the placebo group, however the extremely low significance value across multiple analyses supports the positive treatment effect of peanut SLIT.

In conclusion, peanut SLIT successfully and safely induced desensitization in the majority of one- to four-year-old peanut-allergic children. Almost half of these treated participants also demonstrated remission lasting three months after stopping peanut SLIT therapy. Higher rates of desensitization and remission in the youngest 1–2 year-old group compared to the 2–3 and 3–4 year-old groups supported an advantage to early intervention. Larger trials are necessary to validate these findings in this population.

CLINICAL IMPLICATIONS.

Peanut SLIT is safe in young children with greater likelihood of desensitization and remission with younger age of initiation. Early intervention with peanut SLIT is promising and warrants further development.

ABBREVIATIONS

CTD

cumulative tolerated dose

DBPCFC

double-blind, placebo-controlled food challenge

EPIT

epicutaneous immunotherapy

FARE

Food Allergy Research and Education

IgE

immunoglobulin E

IgG4

immunoglobulin G4

IRB

institutional review board

ITN

Immune Tolerance Network

ITT

intent to treat

NCCIH

National Center for Complementary and Integrative Health

NCI-CTCAE

National Cancer Institute Common Terminology Criteria for Adverse Events

NHLBI

National Heart, Lung and Blood Institute

NIAID

National Institute of Allergy and Infectious Diseases

NIH

National Institutes of Health

OFC

oral food challenge

OIT

oral immunotherapy

PP

per protocol

Pn-sIgE

peanut-specific IgE

Pn-sIgG4

peanut-specific IgG4

SLIT

sublingual immunotherapy

SPT

skin prick test

UNC

University of North Carolina

UTSW

University of Texas Southwestern