| Coverage Policy Manual | |
| Policy #: | 1998038 |
| Category: | Medicine |
| Initiated: | February 1998 |
| Last Review: | November 2023 |
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| Allergy Immunotherapy | |
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| Description: |
Allergen-specific immunotherapy involves administering well-characterized allergen extracts, the potencies of which are measured and compared with a reference standard (Moote, 2018). An initial induction or build-up phase progressively increases the allergen dose; this is followed by years of maintenance injections at the highest dose. Allergen-specific immunotherapy has been used to treat various conditions, including insect allergy, allergic rhinitis, and asthma. Subcutaneous immunotherapy is the standard of care. Due to the inconvenience of multiple injections, particularly in children, alternative delivery routes have been investigated; of these, sublingual immunotherapy is the most prominent. Sublingual immunotherapy targets absorption to the sublingual and buccal mucosa. Allergen preparations used for sublingual immunotherapy are held under the tongue for 1 to several minutes and then swallowed or spit out.
Other methods of allergy immunotherapy include provocative and neutralization therapy for food allergies, using intradermal and subcutaneous routes, urine auto-injections (autogenous urine immunization), repository emulsion therapy, and the Rinkel Method (a low dose immunotherapy). The Rinkel Method was tested on patients with hay fever (Van Metre, 1980) and is also referred to as serial dilution endpoint titration therapy for ragweed pollen hay fever.
Coding
See CPT/HCPCS Code section below.
The CPT codes for allergen immunotherapy are specific to injections and should not be used for sublingual immunotherapy.
Sublingual immunotherapy should be billed through the member’s pharmacy benefit.
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Policy/ Coverage: |
Sublingual immunotherapy should be billed through the member’s pharmacy benefit.
Effective November 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Immunotherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in individuals with demonstrated hypersensitivity that cannot be managed by medications or avoidance. Injections of airborne or insect venom allergens should be prepared for the patient individually.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The following immunotherapy methods do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, the following methods are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to November 2022
Immunotherapy meets primary coverage criteria for effectiveness and is covered in patients with demonstrated hypersensitivity that cannot be managed by medications or avoidance. Injections of airborne or insect venom allergens should be prepared for the patient individually.
The following immunotherapy methods are not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
For contracts without primary coverage criteria, the following methods are considered investigational:
Investigational services are an exclusion in the member certificate of coverage.
Effective Prior to November 2018
Immunotherapy meets primary coverage criteria for effectiveness and is covered in patients with demonstrated hypersensitivity that cannot be managed by medications or avoidance. Injections of airborne or insect venom allergens should be prepared for the patient individually.
The following immunotherapy methods:
are not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria, the following methods:
are considered investigational. Investigational services are an exclusion in the member certificate of coverage.
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| Rationale: |
This policy is updated in 2003 with a focused review of two of the immunotherapy procedures addressed in this policy, sublingual immunotherapy (SLIT) and serial endpoint testing (SET) guided immunotherapy.
Sublingual Immunotherapy
Studies of sublingual immunotherapy (SLIT) or subcutaneous injection of Allergan-specific immunotherapy (ASIT) commonly measure allergic symptoms and use of rescue medications using quantitative scales. Double-blind, placebo-controlled randomized trials have reported attenuated allergic symptoms and reduced medication use after injection ASIT for various allergens. In addition, evidence shows that clinical benefits from multiple years of ASIT persist for several years after injections are discontinued.
Twenty-one placebo-controlled clinical trials met selection criteria. Patient sample size was small in most of them. The predominance of evidence suggested that, when prepared in potencies similar to the available studies and compared with placebo, SLIT decreased one or more symptoms for patients with pollen or dust mite allergies. Systemic side effects occurred in only one study, and these were not life threatening. Evidence on whether SLIT may also reduce use of rescue medications was conflicting and inconclusive.
The established alternative to SLIT has been injection ASIT. Whether SLIT improves health outcomes when compared with injection ASIT could not be determined from the available evidence. The results of 2 trials that directly compared SLIT with injection ASIT were insufficient to permit conclusions. Patient groups in each trial were small (10-15 patients per arm), and each was of short duration. Neither trial followed up patients after immunotherapy was terminated, and thus neither trial speaks to the persistence of possible therapeutic effects.
Serial Endpoint Testing-Guided Immunotherapy
Serial endpoint testing (SET) is a form of intradermal skin testing that uses increasing doses of antigen to determine the concentration at which the reaction changes from negative to positive (the endpoint). SET has also been used to guide the initiation of immunotherapy by using endpoint dilution as a starting antigen dose.
The majority of trials that evaluate SET-guided immunotherapy do not report improved outcomes with SET, as compared to placebo or alternative delivery method. However, the conclusions that can be derived from these data are also limited. The trials are small, do not report power calculations, and do not define the level of improvement of symptoms that is clinically significant. The studies do not use standardized outcome measures and do not report the degree of improvement over the course of study. In many studies, subjective improvement is the main outcome measure used. Furthermore, the same physicians providing treatment assess patient outcome, and no trial uses blinded outcome assessment.
2005 Update
A literature search for the period of 2003 though February 2005 did not identify any published articles that would change the coverage policy statement.
2006 Update
A literature search for the period of February 2005 though August 2006 did not identify any published articles that would change the coverage policy statement.
2007 Update
A literature search of MEDLINE for the period of August 2006 through December 2007 did not identify any published articles that would change the coverage policy statement.
2011 Update
A search of the MEDLINE database was conducted through January 2011. The following is a summary of the identified literature:
A 2010 meta-analysis by Di Bona and colleagues focused on studies of sublingual immunotherapy in adults and children with season allergic rhinitis. To be included in the meta-analysis, trials needed to be double-blind and placebo-controlled and evaluate natural grass pollen extracts used to treat individuals with a history of grass pollen allergy (Di Bona, 2010). The authors identified 19 trials with a total of 2971 patients; the sample size of individual studies ranged from 34 to 578. The primary outcome was treatment effect defined as reduction in symptoms. Because studies used different scoring symptoms, the standardized mean difference (SMD) was calculated. The pooled SMD for treatment effect indicated a significantly greater reduction in symptoms in the sublingual immunotherapy group compared to placebo. The finding was similar when the largest trial was excluded.
Compalati and colleagues, authors of the 2009 review of meta-analyses of randomized trials on sublingual immunotherapy (Compalati, 2009), concluded that meta-analysis suggest that SLIT is effective compared to placebo, but noted that meta-analyses generally provide information about the global efficacy of a treatment, rather than information about specific doses, treatment regimens, etc. In this case, the trials included in the meta-analyses varied widely in terms of the allergens targeted and dosages; optimal dose for any particular allergen remains unknown. The 2010 meta-analysis by Di Bona and colleagues provides data similar to those in the earlier meta-analyses.
Few published randomized trials have compared sublingual immunotherapy and subcutaneous immunotherapy. A 2009 review article by Pipet and colleagues lists four randomized controlled trials that compared SLIT and SCIT; the studies were published between 1996 and 2007 and included between 20–71 participants (Pipet, 2009). None of the 4 studies found a significant difference in efficacy between the 2 routes of administration. In the 2 studies that also included placebo groups, on most outcomes both allergen-specific immunotherapy groups had improved outcomes compared to placebo. An additional study, conducted in Turkey, was published in 2010 (Eifan, 2010). This was a randomized, open-label study and included 48 children with asthma or rhinitis who had been sensitized to house dust mites. Participants were randomized to receive treatment with sublingual immunotherapy (n=16), subcutaneous immunotherapy (n=16), or usual pharmacotherapy alone (n=16). As with the earlier trials, there was no significant difference in efficacy between the sublingual and subcutaneous immunotherapy groups. Compared to pharmacotherapy alone, both immunotherapy groups demonstrated significant reduction in rhinitis and asthma symptom scores and medication use scores.
Review articles have suggested that sublingual immunotherapy may be safer than subcutaneous immunotherapy. The Pipet review cites reports of fatalities after subcutaneous immunotherapy, although subsequent examination of 13 deaths occurring between 1992 and 1996 suggested that unstable asthma was a major risk factor. It is generally believed that subcutaneous immunotherapy is safe when performed with proper patient selection and established security principles. The review authors state that, to date, no fatalities associated with sublingual therapy have been reported.
Summary
Despite additional placebo-controlled studies evaluating sublingual immunotherapy, questions remain about the optimal dosing, duration of treatment, and the use of multiple allergens. Moreover, there are few studies comparing sublingual immunotherapy to subcutaneous immunotherapy. The limited comparative evidence suggests that the two methods of administration have similar efficacy, but firm conclusions cannot be drawn due to variability in study design and limited statistical power. The sample sizes in the comparative studies are also too small to draw conclusions about the relative safety of sublingual and subcutaneous immunotherapy.
2012 Update
A search of the MEDLINE database through August 2012 did not identify any new information that would prompt a change in the coverage statement. A Cochrane review and two meta-analyses were indentified and are summarized below.
A 2011 Cochrane review addressed SLIT for treating allergic conjunctivitis in adults and/or children (Calderon, 2011). A total of 57 trials met inclusion criteria, and 42 of these had data available for meta-analysis. All of the trials were conducted in countries other than the United States. The primary outcome of the meta-analysis was the total ocular symptom score. Because studies used different scoring symptoms, the standard mean difference (SMD) was calculated. In a pooled analysis of data from 36 trials with a total of 3,399 participants, there was a significantly greater reduction in total ocular symptom scores in the SLIT group compared to placebo (SMD: -0.41, 95% confidence interval [CI: -0.53 to -0.28, p<0.0001). This review supports the conclusion that SLIT is moderately effective in reducing ocular symptom scores compared to placebo but that concerns about the overall quality of the evidence base remain.
In 2011, Radulovic and colleagues published a meta-analysis of double-blind, placebo-controlled RCTs on SLIT for allergic rhinitis in adults and/or children (Radulovic, 2011). Sixty studies met inclusion criteria, and 49 (total n=4589) of these had efficacy data available suitable for meta-analysis. Most of the studies (n=23) used grass pollen; other allergens used included ragweed, house dust mites, and trees. In a pooled analysis of study findings, there was a significantly greater reduction in symptom scores with active SLIT treatment compared to placebo (SMD: -0.49, 95% CI: -0.64 to -0.34, p<0.0001). In addition, a pooled analysis found a significantly greater reduction in medication use scores with SLIT versus placebo (SMD: -0.32, 95% CI: -0.43 to -0.21, p<0.0001).
In 2011, Sieber and colleagues published a meta-analysis of individual patient data from 4 observational studies on treatment of allergic rhinitis (Sieber, 2011). A total of 665 patients were treated with SLIT and 182 with SCIT. The median rhinitis symptom score decreased from 3.00 to 2.00 (range 1.00 to 4.00) in both treatment groups; p<0.001 for changes within-group. The median conjunctivitis symptom score decreased from 2.00 to 1.00 (range 0.00-3.00) in each group; p<0.001 for changes within-group. In addition, the median asthma symptom score decreased from 3.00 to 2.00 (range 1.00-4.00) in each group; p<0.001 for changes within-group. There were no significant differences in symptom scores when the SLIT group was compared to the SCIT group.
The Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma and Immunology (AAAAI); the American College of Allergy, Asthma, and immunology (ACAAI); and the Joint Council of Allergy, Asthma, and Immunology (JCAAI) published a third update (Cox, 2011). The update included the following information regarding allergy immunotherapy which does not prompt a change in the coverage statement:
2015 Update
A literature search conducted through April 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2014, Devillier and colleagues in France published a systematic review with meta-analyses of SLIT and pharmacotherapy for seasonal allergic rhinitis (Devillier, 2014). Only well powered (≥ patients in the smaller treatment arm), placebo-controlled, randomized trials were included (N=28 pharmacotherapy trials and 10 SLIT trials; total number of patients = 21,223). Studies evaluated children and adults. Because of methodologic heterogeneity across trials (eg, in symptom scales used), results from individual trials were standardized relative to placebo effects to permit meta-analysis. Pooled percentage improvements in symptom scores were: 30% for 5-grass pollen SLIT, 24% for nasal corticosteroids, 19% for timothy pollen SLIT, 17% for combination azelastine fluticasone, 15% for H1-antihistamines, and 7% for montelukast.
House Dust Mite-Specific Allergy
Several placebo-controlled RCTs published in 2013 and 2014 assessed house dust mite (HDM)-SLIT in children and adults sensitized to HDM (primarily Dermatophagoides species) who have rhinitis(Aydogan, 2013; Wang, 2013; Bergmann, 2014; Nolte, 2015), and/or asthma (Tian, 2014; Mosbech, 2014; ; de Blay, 2014; Wang, 2014). HDM-SLIT generally showed statistically significant reductions in rhinitis symptom scores in these trials, with reductions of approximately 20% in one study,41 and a statistically significant decrease in daily dose of inhaled corticosteroid in HDM-sensitized patients with mild-to-moderate asthma (Mosbech, 2014; de Blay, 2014).
In 2014, Gendelman and Lang published a systematic review of HDM-SLIT in atopic dermatitis (Gendelman, 2015). Five studies (N=344) were identified, but low methodologic quality limited conclusions that could be drawn.
Food Allergy
Three-year follow-up of a placebo-controlled RCT (Fleischer, 2013) showed a high rate of dropout (>50%) and sustained responsiveness in only 4 (11%) of 37 SLIT-treated patients (Burks, 2015). A 2014 systematic review of the literature through September 2012 identified 5 randomized trials of SLIT in patients with food allergies, 4 of which showed symptom improvement compared with placebo (de Silva, 2014). However, all trials were considered low quality; for example, most did not include symptom assessments off treatment. In a subsequently published, small, double-blind RCT, Narisety et al (2014) showed greater efficacy of oral immunotherapy compared with SLIT in 21 patients with peanut allergy (Narisety, 2014).
In 2014, Romantsik et al reported on a Cochrane review of oral immunotherapy and SLIT for egg Allergy (Romantsik, 2014). No RCTs of SLIT were identified through November 2013.
Allergic Rhinoconjunctivitis and Asthma
Two indirect comparative effectiveness analyses published in 2014 and 2015 reached similar conclusions regarding relative efficacy of SLIT and SCIT for grass pollen allergies (Dranitsaris, 2014; Nelson, 2015). Both studies showed comparable reductions in allergic rhinitis symptoms with SLIT and SCIT, and 1 study showed comparable reductions in medication use (Nelson. 2015). Both studies found evidence for publication bias.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov found 9 active trials of SLIT for allergies. These are summarized below.
The first trial listed (NCT01335139) compares SLIT with SCIT using a double-placebo design in patients with seasonal allergic rhinitis. Several studies investigate HDM SLIT, and 1 (NCT02052934) investigates SLIT for enterotoxigenic Escherichia coli.
Active Trials of Sublingual Immunotherapy for Allergies
Seasonal Allergic Rhinitis
(NCT01335139) A Randomized , Double-blind, Single Center, Placebo Controlled Study of Sublingual immunotherapy and Subcutaneous Immunotherapy in Adults With Seasonal Allergic Rhinitis ((ITN043AD); age group adult; phase 2; estimated number 90; projected primary completion date September 2014.
(NCT02014623) Immunological Mechanisms of Oralair® (5 Grass Mix Sublingual Allergen Immunotherapy Tablet) on Patients With Seasonal Allergic Rhinitis; age group child, adult; phase 4 estimated number 40; projected primary completion date May 2015.
(NCT02005627) Randomized Placebo-controlled Study of Grass Pollen Allergen Immunotherapy Tablet (AIT) for Seasonal Rhinitis: Time Course of Nasal, Cutaneous and Immunological Outcomes; age group adult; phase 2; estimated number 44; projected primary completion date March 2017.
House Dust Mite-Induced Allergic Rhinitis
(NCT0170012) A One-year Placebo-Controlled Study Evaluating the Efficacy and Safety of the House Mite Sublingual Allergen Immunotherapy Tablet (SCH 900237/MK8237) in Children and Adult Subjects With House Dust Mite-Induced Allergic Rhinitis/Rhinoconjunctivitis With or Without Asthma (Protocol No. P05607/001); age group child, adult and senior; phase 3; estimated number 1500; projected primary completion date February 2015.
(NCT01852825) A Two Part, Randomized Clinical Trial to Study Biomarkers of MK-8237) Treatment in Subjects With House Dust Mite Induced Allergic Rhinitis or Rhinoconjunctivitis; age group adult; phase 1; estimated number 34; projected primary completion date June 2015.
(NCT02277483) Efficacy and Safety of LAIS® Mites Sublingual Tablets in Patients Aged Over 60 Years Suffering From House Dust Mite-induced Allergic Rhino-conjunctivitis With/Without Asthma; age group adult; phase 4; estimated number 45; projected primary completion date December 2016.
Food Allergies
(NCT02304991) Peanut Sublingual Immunotherapy Induction of Clinical Tolerance of Newly Diagnosed Peanut Allergic 12 to 48 Month Old Children; aged group child; phase 2; estimated number 50; projected primary completion date April 2020.
(NCT01373242) Peanut Sublingual Immunotherapy and Induction of Clinical Tolerance in Peanut Allergic Children; aged group child; phase 1|2; estimated number 53; projected primary completion date June 2021.
(NCT02216175) Phase 2/3 Clinical Trial to Assess the Effect of a Sublingual Treatment Phase Prior to Oral Immunotherapy in Children With Cow's Milk Allergy; age group child; phase 2|3; estimated number 53; projected primary completion date May 2017.
(NCT00732654) The Safety and Efficacy of Sublingual/Oral Immunotherapy for the Treatment of Milk Protein Allergy; age group child; phase 1|2; estimated number 30; projected primary completion June 2015.
EAACI
In 2014, EAACI published evidence-based guidelines on the diagnosis and management of food allergy (Muraro, 2014). Based on single-arm studies (Level III evidence), guideline authors concluded, “Food allergen-specific immunotherapy for primary food allergy is a promising immunomodulatory treatment approach, but it is associated with risk of adverse reactions, including anaphylaxis; it is therefore not currently recommended for routine clinical use.” Based on expert opinion (Level IV evidence), guideline authors stated, “For patients with respiratory or other allergy symptoms to inhalant allergens that may also cause cross-reactive food allergy, specific immunotherapy is only recommended for the treatment of the respiratory symptoms, not for cross-reactive food allergy.”
American Academy of Otolaryngology – Head and Neck Surgery Foundation
In 2015, the American Academy of Otolaryngology – Head and Neck Surgery Foundation published evidence-based consensus guidelines on allergic rhinitis (Seidman, 2015). Based on RCTs and systematic reviews showing greater benefit than harm, guideline developers recommended SLIT or SCIT “for patients with allergic rhinitis who have inadequate response to symptoms with pharmacologic therapy with or without environmental controls.” The purpose of the statement was “to increase the awareness of immunotherapy as a treatment for allergic rhinitis, promote its appropriate use, and reduce unnecessary or harmful variation in care.”
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2014, FDA approved 3 sublingual allergen products for treatment of allergic rhinitis or rhino conjunctivitis. A 2015 systematic review and meta-analysis by Di Bona and colleagues published a meta-analysis of studies on FDA-approved grass pollen SLIT tablets (Di Bona, 2015). Thirteen studies met reviewers’ inclusion criteria, which were placebo-controlled randomized controlled trials (RCTs) on grass pollen SLIT in patients with a clinical history of seasonal allergic rhino conjunctivitis and data on symptom scores or medication scores. Most studies reported the same symptom score, which ranged from 0 to 18 points (higher scores indicating greater disease severity). In a pooled analysis of study data, SLIT was more effective than placebo. The standardized mean difference for the treatment effect was -0.28 (95% confidence interval [CI], -0.37 to -0.19; p<0.001). Findings were similar in an analysis that excluded the 5 studies at high or moderate risk of bias.
A 2015 meta-analysis by Didier and Bons reviewed safety data on Oralair (Didier, 2015). The reviewers reported on 2 post-marketing safety studies. A 2008 study was conducted in 808 adults and 91 children and adolescents treated for a mean of 191 days. A total of 320 (36%) of patients experienced an adverse drug reaction (ADR). A 2009 study was conducted in 829 children and adolescents treated for a mean of 190 days, and 218 (27%) patients experienced an ADR. ADRs led to medication discontinuation in 85 (9.5%) patients treated in 2008 and 72 (9.0%) patients treated in the 2009 study. In both studies combined, 9 serious ADRs possibly related to the medication were reported.
A 2015 study by Maloney and colleagues analyzed safety data from 8 placebo-controlled trials on Grastek (Maloney, 2015). There were 4195 patients in the pooled study population, 3314 adults and 881 children and adolescents. A total of 2115 were treated with grass SLIT tablets. Eight (0.4%) SLIT-treated patients experienced a mild or moderate systemic allergic reaction; no serious systemic allergic reactions were reported. Sixteen (1.6%) SLIT-treated patients reported treatment-related severe local allergic swellings. These comprised mouth edema, oropharyngeal swelling, palatal edema, pharyngeal edema, tongue edema, swollen tongue, throat tightness, and laryngeal edema.
In 2015, Liao and colleagues published a meta-analysis of studies on dust mite SLIT for treating children with asthma (Liao, 2015). The reviewers identified 11 RCTs and prospective controlled studies evaluating SLIT in children (ie, <18 years old) with asthma and reporting clinical outcomes. Studies compared SLIT to placebo and/or pharmacotherapy. Findings of the meta-analysis were mixed. A pooled analysis of 8 studies found that an asthma symptom score decreased significantly more in the SLIT groups than in the control groups (SSD = -1.20; 95% CI, -2.07 to -0.33; p=0.007). A pooled analysis of 3 studies did not find significant differences between groups in change in medication usage (SSD = -0.52; 95% CI, -1.753 to 0.713; p=0.408). Groups also did not differ significantly in an analysis of change in specific Dermatophagoides pteronyssinus IgE levels before and after treatment (SSD=0.430; 95% CI, -0.045 to 0.905; p=0.076). In all analyses, there were high levels of heterogeneity among studies.
Randomized Controlled Trials
Several RCTs have been published since the systematic reviews. In 2015, Narisety published a double-blind RCT comparing oral immunotherapy and SCIT in 21 children with peanut allergies (Narisety, 2015). Five (24%) children dropped out. Among the remaining 16 patients, those in the oral immunotherapy group had a significantly greater challenge threshold at 12 months than those in the SCIT group (p=0.01). However, only 4 patients had sustained unresponsiveness. Adverse events, generally mild, were significantly more common in the oral immunotherapy group. A 2015 RCT by Burks and colleagues reported on a placebo-controlled SLIT study in 40 patients (20 per group) with peanut allergy (Burks, 2015). At week 44, 14 (70%) in the SLIT group were considered responders compared with 3 (15%) in the placebo group. Seventeen patients in the placebo group crossed over to receive high-dose SLIT and 7 (44%) were considered responders after 44 weeks.
No trials comparing SLIT and SCIT for treatment of food allergies were identified.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Grazax
A 2017 double-blinded, placebo-controlled randomized trial by Scadding et al enrolled 106 adults with moderate-to-severe seasonal allergic rhinitis at a single center to determine whether 2 years of SLIT improved symptoms at the 3-year follow-up, 1 year after discontinuation of treatment (Scadding, 2017). Patients were randomized to SLIT with placebo, SCIT with placebo, or double-placebo, and 92 patients completed the study overall. The primary end point was measurement of the Total Nasal Symptom Score (TNSS; range 0 [best] to 12 [worst] within 10 hours of the challenge) after a nasal response challenge at 3-year follow-up. Although the ITT population included all randomized patients, only those with an evaluable endpoint were included in the analysis (modified ITT).
The reported between-group difference was -0.18 (95% CI, -1.25 to 0.90; p=0.75), adjusted for baseline, demonstrating no statistically significant improvement in the primary outcome compared with placebo.
Secondary end points included a change in peak nasal inspiratory flow after challenge, seasonal weekly visual analog scale score, seasonal weekly rhinitis quality of life, end-of-season global rhinitis severity score, seasonal medication use, and early and late skin responses to intradermal allergen. There was no benefit from SLIT or SCIT compared with placebo for peak nasal inspiratory flow, visual analog scale scores, seasonal weekly rhinitis quality of life, or global rhinitis severity score. Throughout the 3 years, approximately 90% of participants returned some medication, and 47% to 70% returned all medication. At year 3, however, there were no significant between-group differences in medication use. Both SLIT and SCIT had lower early and late skin responses to allergen than placebo. Although there were no serious adverse effects from treatment, the SCIT group had a greater number of adverse events overall.
Statistically significant differences between SLIT and placebo included hypersensitivity (p=0.19) and dyspepsia (p=0.03).
Researchers reported several limitations. To avoid seasonal variability in natural pollen exposure, the trial used the nasal allergen challenge in a controlled environment rather than daily symptom diaries. The trial focused on intervention effects for 2 years only and was not designed to compare 2 with 3 years of SLIT. Though the trial was not powered to compare SLIT with SCIT, and dropout rates were similar among the 3 groups, adherence was greater in the SLIT group (>90%) compared with the SCIT group (82%). Because blinding may have been compromised in patients in the placebo groups who experienced adverse effects, an individual who was not involved in seasonal assessments or the clinical immunotherapy protocol performed all nasal challenges and skin tests.
The largest pediatric trial to date by Valvorita et al assessed the impact of SLIT on grass pollen allergic rhinoconjunctivitis symptoms, medication use, immunologic markers, and notably, the onset of asthma (Valvorita, 2017). The 5-year double-blind, placebo-controlled trial with 2 years of follow-up was conducted at 101 sites in 11 European countries and enrolled 812 children ages 5 to 12 with a history of allergic rhinoconjunctivitis (mean, 3.4 years). Of those randomized, 608 (75%) completed the trial.
There was no difference in time to onset of asthma (primary end point) between the SLIT group (n=398) and the placebo group (n=414). However, there was a 71% relative risk reduction in asthma symptoms and asthma medication use for the entire trial period and for the 2-year follow-up period (odds ratio, 0.28; p<0.001). Assessment of secondary end points is as follows. During the 3 years of treatment and 2 follow-up years, the SLIT group had a 22% to 30% reduction in allergic rhinoconjunctivitis symptoms when compared with placebo (p<0.002). Visual analog scale scores revealed a 22% reduction in symptoms for the SLIT group compared with the placebo group (p=0.005). The SLIT group also had a 27% reduction in medication use relative to the placebo group (p<0.001).
The most frequently reported adverse effects were nasopharyngitis, allergic conjunctivitis, oral pruritus, cough, and gastroenteritis. Compared with placebo, a higher proportion of children in the intervention group dropped out due to adverse effects. However, the study identified no new safety concerns. The authors reported no limitations to the RCT.
A 2017 meta-analysis of placebo-controlled randomized trial by Feng et al evaluated the efficacy and safety of SLIT use in pollen-induced allergic rhinitis in children ages 3 to 18 years (Feng, 2017). Of the 26 eligible RCTs (published 1990 to 2016), 14 (1475 patients) studied symptom reduction, and 12 (1196 patients) examined medication use. Only the subgroup analysis evaluated the use of SLIT for the population of interest, thereby rendering the overall results of the meta-analysis beyond the scope of this evidence review.
Nasal symptom and medication scores were assessed using mean differences and SMD.
Although the meta-analysis overall demonstrated a significant reduction in symptoms and medication use for pediatric patients, the subgroup analysis found that that SLIT was effective for grass pollen-induced allergic rhinitis only. Overall, oral pruritus was the most common adverse effect in children who were receiving SLIT. Although the study addressed heterogeneity and potential of bias overall, neither was specifically reported for the studies included in the subgroup analysis.
In 2017, Feng et al also conducted a meta-analysis of 25 placebo-controlled randomized trials (published from 1990 to 2016) on the efficacy of SLIT for dust mite-induced allergic rhinitis in adults and children (Feng, 2017). Most trials were double-blinded and deemed to be of high quality. All studies compared the intervention with placebo for a period that ranged from 6 to 36 months. In total, there were 3674 randomized patients, and the largest trial included 992 participants. There were 12 pediatric trials, with ages ranging from 3 to 18 years. The RCTs included participants from Europe (13 studies, n=2845 patients), Eastern Asia (5 studies, n=590 patients), Western Asia (5 studies, n=149 patients), Oceania (1 study, n=30 patients), and Africa (1 study, n=60 patients). Of 23 studies that reported discontinuation rates, 539 (14.6%) participants dropped out due to the following: adverse effects (3.0%), loss to follow-up (2.0%), noncompliance (1.9%), and poor efficacy (0.9%).
Primary end points were symptom scores and medication use. Symptom scores varied by type, including rhinitis symptoms only, rhinoconjunctivitis symptoms, or rhinoconjunctivitis and asthma symptoms. Overall, there was a significant reduction in symptoms in the SLIT group relative to placebo (SMD=1.23; 95% CI, 1.74 to 0.73; p<0.001). A subgroup analysis of trials using different modalities (drops, n=19; tablets, n=6) found a significant reduction in symptom scores with the use of tablets (SMD = -1.81; 95% CI, -2.94 to -0.68; p=0.002) relative to drops (SMD = -1.06; 95% CI, -1.67 to -0.44; p<0.001). Medication type also varied, including systemic and topical antihistamines, decongestants, and both systemic and topical nasal corticosteroids. Data on medication use was available in 18 RCTs, but the final analysis included only 15 RCTs due to substantial differences in how data were evaluated. Overall, there was a significant reduction in medication use in the SLIT group relative to the placebo group (SMD = -1.39; 95% CI, -1.90 to -0.88; p<0.001). Additionally, the significant reductions in medication use found among adults were not found in children (p=0.060), possibly due to dosage, lack of compliance, or small sample size.
Reviewers pointed out several important limitations to the meta-analysis, including significant heterogeneity among studies, inadequate reporting of blinding procedures, potential publication bias, small sample sizes, and variations in assessment scores, study protocols, pharmaceutical preparations, baseline symptom severity, and the prevalence of respiratory allergic complications among patients. A SMD measure, a random-effects model, and sensitivity analysis were used to mitigate these limitations.
In an additional subgroup analysis included in the 2017 review of placebo-controlled randomized trials, Feng et al also evaluated the efficacy and safety of SLIT use in pollen-induced allergic rhinitis in children ages 3 to 18 years (Feng, 2017). Of the 26 eligible RCTs (published 1990 to 2016), 12 studies (737 patients) studied symptom reduction, and 7 studies (359 patients) examined medication use in house dust mite-induced allergic rhinitis. Only the subgroup analysis evaluated the use of SLIT for the population of interest, thereby rendering the overall results of the meta-analysis beyond the scope of this evidence review.
Nasal symptom and medication scores were assessed using mean differences and SMD. There was no statistically significant reduction in symptoms or medication use for children with house dust mite-induced allergic rhinitis.
Overall, oral pruritus was the most common adverse effect in children who were receiving SLIT. Although the meta-analysis addressed heterogeneity and potential of bias overall, these were not specifically reported for the studies included in the subgroup analysis.
Clinical Trials
Clinical trial results continue to support present position:
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Pollen-Induced Allergic Rhinitis or Rhinoconjunctivitis
A TEC Assessment concluded that, due to the paucity of studies comparing SLIT with subcutaneous immunotherapy (SCIT) and the lack of U.S. Food and Drug Administration (FDA)-approved agents for use in SLIT, the evidence was insufficient on the use of SLIT for allergen immunotherapy (TEC, 2003). Evidence and regulatory approval have progressed since the 2003 TEC Assessment.
The meta-analysis by Yang et al evaluated the use of SLIT to treat allergic conjunctivitis (AC) or allergic rhinoconjunctivitis (ARC) in patients aged 3 to 18 years, specifically looking for SLIT’s effectiveness for relieving eye symptoms (Yang, 2018). Thirteen randomized clinical trials were identified, which included a total of 1592 pediatric patients. Overall, the trials showed that AC symptoms were significantly reduced by SLIT (standardized mean difference [SMD] = -0.21; 95% CI, -0.41 to -0.01; p=0.04; I 2 = 55%). However, on a subgroup analysis of the different SLIT modalities, ocular symptoms improved with tablets (p < 30) of 46% of the studies. However, their results showed that SLIT effectively reduced conjunctivitis symptoms in pediatric patients with AC and ARC.
SLIT vs SCIT
Grastek
On April 11, 2014, Grastek was approved in the U.S. for use in individuals 5 to 65 years of age. Grastek is indicated as immunotherapy for the treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis as confirmed by positive skin tests or in vitro testing for pollen-specific IgE antibodies for Timothy grass or cross-reactive grass pollens. The product was first approved under the trade name Grazax in Sweden and has subsequently received marketing authorizations in 31 countries.
Grazax
A double-blinded, placebo-controlled randomized trial by Scadding et al enrolled 106 adults with moderate-to severe seasonal allergic rhinitis at a single-center to determine whether 2 years of SLIT improved symptoms at the 3- year follow-up, 1 year after discontinuation of treatment (Scadding, 2017). Patients were randomized to SLIT with placebo, SCIT with placebo, or double-placebo; 92 patients completed the study overall. The primary endpoint was the measurement of the Total Nasal Symptom Score range 0 [best] to 12 [worst] within 10 hours of the challenge) after a nasal response challenge at 3-year follow-up. Although the intention-to-treat population included all randomized patients, only those with an evaluable endpoint were included in the analysis (modified intention-to-treat).
The reported between-group difference was -0.18 (95% CI, -1.25 to 0.90; P=0.75), adjusted for baseline, demonstrating no statistically significant improvement in the primary outcome compared with placebo.
Secondary endpoints included a change in peak nasal inspiratory flow after challenge, seasonal weekly visual analog scale score, seasonal weekly rhinitis quality of life, end-of-season global rhinitis severity score, seasonal medication use, and early and late skin responses to intradermal allergen. There was no benefit from SLIT or SCIT compared with placebo for peak nasal inspiratory flow, visual analog scale scores, seasonal weekly rhinitis quality of life, or global rhinitis severity score. Throughout the 3 years, approximately 90% of participants returned some medication, and 47% to 70% returned all medication. At year three, however, there were no significant between-group differences in medication use. Both SLIT and SCIT had lower early and late skin responses to allergen than placebo. Although there were no serious adverse events from treatment, the SCIT group had a greater number of adverse events overall. Statistically significant differences between SLIT and placebo included hypersensitivity (P=0.19) and dyspepsia (P =0.03).
Researchers reported several limitations. To avoid seasonal variability in natural pollen exposure, the trial used the nasal allergen challenge in a controlled environment rather than daily symptom diaries. The trial focused on intervention effects for two years only and was not designed to compare two with three years of SLIT. Though the trial was not powered to compare SLIT with SCIT, and dropout rates were similar among the 3 groups, adherence was greater in the SLIT group (>90%) compared with the SCIT group (82%). Because blinding may have been compromised in patients in the placebo groups who experienced adverse events, an individual who was not involved in seasonal assessments or the clinical immunotherapy protocol performed all nasal challenges and skin tests.
The largest pediatric trial to date by Valvorita et al assessed the impact of SLIT on grass pollen allergic rhinoconjunctivitis symptoms, medication use, immunologic markers, and notably, the onset of asthma (Valvorita, 2018). The 5-year double-blind, placebo-controlled trial with 2 years of follow-up was conducted at 101 sites in 11 European countries and enrolled 812 children ages 5 to 12 with a history of allergic rhinoconjunctivitis (mean, 3.4 years). Of those randomized, 608 (75%) completed the trial.
There was no difference in time to onset of asthma (primary endpoint) between the SLIT group (n=398) and the placebo group (n=414). However, there was a 71% relative risk reduction in asthma symptoms and asthma medication use for the entire trial period and for the 2-year follow-up period (odds ratio, 0.28; P<0.001). Assessment of secondary endpoints is as follows. During the 3 years of treatment and 2 follow-up years, the SLIT group had a 22% to 30% reduction in allergic rhinoconjunctivitis symptoms compared with placebo (P<0.002). Visual analog scale scores revealed a 22% reduction in symptoms for the SLIT group compared with the placebo group (P=0.005). The SLIT group also had a 27% reduction in medication use relative to the placebo group (P<0.001).
The most frequently reported adverse events were nasopharyngitis, allergic conjunctivitis, oral pruritus, cough, and gastroenteritis. Compared with placebo, a higher proportion of children in the intervention group dropped out due to adverse events. However, the trial identified no new safety concerns. The authors reported no limitations to the RCT.
A meta-analysis of placebo-controlled randomized trials by Feng et al evaluated the efficacy and safety of SLIT use in pollen-induced allergic rhinitis in children ages 3 to 18 years (Feng 2017). Of the 26 eligible RCTs (published 1990 to 2016), 14 (1475 patients) studied symptom reduction, and 12 (1196 patients) examined medication use. Only the subgroup analysis evaluated the use of SLIT for the population of interest, thereby rendering the overall results of the meta-analysis beyond the scope of this evidence review. Nasal symptom and medication scores were assessed using mean differences and SMD.
Although the meta-analysis overall demonstrated a significant reduction in symptoms and medication use for pediatric patients, the subgroup analysis found that that SLIT was effective for grass pollen-induced allergic rhinitis only. Overall, oral pruritus was the most common adverse event in children who were receiving SLIT. Although the trial addressed heterogeneity and potential of bias overall, neither was specifically reported for the studies included in the subgroup analysis.
Results of the trial titled “Sublingual Immunotherapy for Peanut Allergy and Induction of Tolerance (SLIT-TLC)” (NCT01373242) are posted on clinicaltrials.gov but have not yet been published. Fifty-four participants aged ≤18 years received peanut SLIT upon enrollment for ≥48 months at which point they underwent a desensitization double-blind placebo-controlled food challenge. After the double-blind placebo controlled food challenge, participants were then randomized to be off treatment for 1-17 weeks, and then underwent a final double-blind placebo-controlled food challenge. Two of the primary outcomes were population sensitization thresholds in mg peanut protein to provoke reactions in 5% and 10% of the peanut-allergic population over 48-52 months. These outcomes also gave the no observed adverse event level and the lowest observed adverse event level, which defined intervals of consecutive administered dose levels where the population sensitization threshold lay. At 5% of the peanut-allergic population, the no observed adverse event level and lowest observed adverse event level were 160 mg and 300 mg, respectively. At 10%, they were 800 mg and 750 mg, respectively. Fifty-three out of 54 participants experienced adverse effects. Thirty-eight participants completed the study (70%).
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A second systematic review assessing the effect of SLIT on house dust mite-induced allergic rhinitis only included studies conducted in children aged 4 to 18 years (Chen, 2020). The review included 16 placebo-controlled trials (N=1,929) of SLIT drops or tablets for 6 to 24 months. Pooled outcomes included nasal symptom, medication, and ocular symptom scores. The review did not report discontinuation rates. Nasal symptom scores, reported in 16 studies, were significantly lower with SLIT versus placebo (SMD -1.73, 95% CI -2.62 to -0.84), but heterogeneity was very high (I2=98%). Total medication scores were also significantly lower with SLIT versus placebo based on evidence from 11 studies (SMD -1.21, 95% CI -1.75 to -0.67), but again heterogeneity was high (I2=94%). For both outcomes, the review found evidence of publication bias, but even after adjustment for bias, SLIT was more effective than placebo for both outcomes, p=0.02 and <0.0001, respectively. Ocular symptom scores were only reported in 6 of the studies. When pooled there was no clear difference between SLIT and placebo (p=0.31), however subgroup analysis found SLIT tablets (SMD -0.28, 95% CI -0.42 to -0.14) more effective than SLIT drops (SMD 0.13, 95% CI -0.20 to 0.60), relative to placebo.
Long-term, open-label follow-up of an RCT included in the da Silva systematic review assessing the effect of SLIT on peanut allergy reported a similar proportion of patients with sustained unresponsiveness (10/48; 21%) similar to the results of the 2015 double-blind RCT by Narisety that was discussed previously (Kim, 2019).
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A separate trial comparing Ragwitek with placebo was conducted by Nolte et al in 1,025 children age 5 to 18 years with ragweed allergic rhinitis, with or without conjunctivitis (Nolte, 2020). Additional inclusion criteria were positive serum IgE to ragweed pollen, and baseline forced expiratory volume in 1 second of at least 80% of predicted. The mean age of trial participants was 12 years, and about half (43%) had concomitant asthma. The study found significant differences favoring Ragwitek over placebo in daily symptom score, daily medication score and total combined score over the course of ragweed pollen season. Results were consistent across the 3 pollen seasons included in the trial and among patients with comorbid asthma. No study relevance or design and conduct limitations were noted.
The pooled FDA safety database comprised 1,057 adults who received at least 1 dose of Ragwitek. The most common TEAEs in this group were throat irritation (17% vs. 3%), oral pruritus (11% vs. 2%), ear pruritus (10% vs. 1%), and oral paresthesia (10% vs. 4%), all versus the placebo group. Four percent and 0.8% of Ragwitek-treated and placebo-treated patients, respectively, discontinued treatment due to adverse reactions. Among Ragwitek-treated patients, the most common adverse reactions that led to study discontinuation were oral edema, swollen tongue, and dysphagia.
In trials 1 and 2 (n=962 Ragwitek-treated patients), no deaths, systemic allergic reactions, or life-threatening events occurred. TEAEs tended to occur early in the treatment course (within the first week or weeks). Most (82% in trial 1, 96% in trial 2) TEAEs were mild to moderate in severity. In trial 2, the most frequently reported adverse event leading to discontinuation was swollen tongue (n=10); all assessed as mild or moderate in severity. One patient required epinephrine for what was considered a progression of treatment-related local reactions.
In the trial conducted in patients aged 5 to 18 years, serious adverse events were rare in both the Ragwitek and placebo groups (0.6% vs. 0.2%), though patients in the Ragwitek group had higher adverse event rates, including throat irritation (48.5%), oral pruritus (47.6%), and ear pruritus (33.9%) compared with patients in the placebo group (18.1%, 11.6% and 6.3%, respectively) (FDA, 2021; Nolte, 2020).
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A meta-analysis by Meltzer et al evaluated SLIT tablets and pharmacotherapy for allergic rhinitis in pediatric and adult patients (Meltzer, 2021). Patients receiving SLIT were allowed rescue symptom-relieving pharmacotherapy in all trials. In adults and adolescents, the mean difference in total nasal symptom score (TNSS) between SLIT tablets and placebo was 0.57 (95% confidence interval [CI], 0.41 to 0.73) for patients with seasonal allergic rhinitis (n=4 trials) and 0.65 (95% CI, 0.42 to 0.88) for patients with perennial allergic rhinitis (n=3 trials). No trials for perennial allergic rhinitis in pediatric patients were found, but 2 trials in pediatric patients with seasonal allergic rhinitis found improved TNSS scores with SLIT tablets compared with placebo (mean difference, 0.53; 95% CI, 0.19 to 0.87). Although not directly compared, the percentage improvement with SLIT was similar to that of intranasal corticosteroids.
An updated systematic review of 7 RCTs in patients with allergic rhinitis by Tie et al failed to find a difference between SLIT or SCIT (Tie, 2022). The authors also conducted an indirect comparison of trials evaluating SCIT versus placebo (n=13) or SLIT versus placebo (n=33), and found no significant differences between SCIT and SLIT.
Kim et al published a network meta-analysis comparing SCIT with SLIT in patients with a house dust mite allergy (Kim, 2021). A total of 26 RCTs (N=6743) were included. Ten studies (n=5744) with SLIT tablets found significant improvement in symptom scores with SLIT compared with placebo (SMD, -0.329; 95% CI, -0.426 to -0.231; p<.01) while 9 studies (n=5725) found improvement in medication score (SMD, -0.227; 95% CI, -0.371 to -0.083; p<.01). The SCIT group had greater efficacy in the symptom score compared with SLIT tablets in network meta-analysis (SMD, -0.819; 95% CI, -1.242 to -0.397). Medication scores were also improved with SCIT (SMD, -0.517; 95% CI, -0.914 to -0.121). The analysis is limited by high levels of heterogeneity in the SLIT studies.
In 2020, the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI) recommended allergen immunotherapy (either subcutaneous immunotherapy [SCIT] or sublingual immunotherapy [SLIT]) be offered to patients with moderate or severe allergic rhinitis who are not controlled with allergen avoidance or pharmacotherapy; prefer immunotherapy; or those who may benefit due to comorbid conditions such as asthma (Dykewicz, 2020).
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Kim et al performed an open-label study of the safety, efficacy, and persistence of desensitization associated with SLIT in pediatric patients aged 1 to 11 years with peanut allergy (Kim, 2023). Patients received sublingual peanut protein in a build-up phase over approximately 5 months to a target maintenance dose of 4 mg once daily; treatment continued for a total of 48 months. Reaction thresholds to peanut were assessed by double-blind, placebo-controlled food challenges performed at baseline (as part of study screening), after 48 months of SLIT, and after a subsequent randomly-assigned avoidance phase of 1 to 17 weeks of peanut and SLIT avoidance. Clinically significant desensitization was defined as a successfully consumed peanut dose of at least 800 mg. Among 54 participants who received SLIT, mean age was 7.1 years; 47 participants completed SLIT and were included in the per-protocol analysis of desensitization at 48 months. Mean successfully consumed peanut dose increased significantly between baseline (48.4 ±93.2 mg) and 48 months (2723 ±1904 mg; p<.0001), with clinically significant desensitization achieved in 70.2% and no reaction throughout SLIT in 36% of participants. Among 37 patients who completed the post-SLIT avoidance phase, median estimated time to loss of clinically significant desensitization was 22 weeks. Dosing symptoms (e.g., oropharyngeal itching, lip swelling) were reported with 4.0% of home-administered doses; antihistamines were administered for symptoms associated with 0.14% of total doses administered and no epinephrine was administered. Three patients withdrew from the study after initiating SLIT due to abdominal side effects.
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