Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis: The GRASS Randomized Clinical Trial

Abstract

Importance: Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.

Objective: To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.

Design, setting, and participants: A randomized double-blind, placebo-controlled, 3-parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015.

Interventions: Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation).

Main outcomes and measures: Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy.

Results: Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was -0.18 (95% CI, -1.25 to 0.90; [P = .75]).

Conclusions and relevance: Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.

Trial registration: clinicaltrials.gov Identifier: NCT01335139; EudraCT Number: 2010-023536-16.

Figure 1

CONSORT diagram. Participant numbers at enrolment, randomization, treatment, follow-up, and for analysis of the primary endpoint (nasal challenge). Eligibility and baseline assessments were completed from September 2011 to January 2012. The last participant completed the study in February 2015. Reasons for drop-outs are indicated. The Intent-to-treat (ITT) sample was defined as all randomized participants. If participants dropped out post-randomization, they were invited to complete study assessments throughout the duration of the trial. The modified ITT population included all randomized participants with an evaluable outcome. The Per-protocol (PP) sample was defined as ITT sample participants who remained in the study for at least 3 years and in whom the primary endpoint was assessed. Participants in the PP sample had to be compliant with study medication, defined as taking 50% or more of their study medication for the duration of the study.

Figure 2

Time-course of changes after nasal allergen challenge for total nasal symptom scores (TNSS scale 0–12, top panel) and peak nasal inspiratory flow (PNIF, lower panel). Data are mean values for participants treated with Sublingual immunotherapy (green), Subcutaneous immunotherapy (red), and Placebo (blue) during years 1 and 2 (on treatment) and year 3 (1 year follow up). TNSS and PNIF were analyzed in the modified Intent-To-Treat Population comprising: 34 Sublingual immunotherapy participants, 33 Placebo participants, and 33 Subcutaneous immunotherapy participants at year 1; 31 Sublingual immunotherapy participants, 32 Placebo participants, and 32 Subcutaneous immunotherapy participants at year 2; 30 Sublingual immunotherapy participants, 31 Placebo participants, and 31 Subcutaneous immunotherapy participants at year 3. Top Panel: A higher total nasal symptom score (TNSS) indicates a higher burden of symptoms during the nasal challenge. Mean (95% Confidence intervals) scores for the TNSS for sublingual immunotherapy, placebo and subcutaneous immunotherapy groups, respectively, at baseline and years 1, 2 and 3 were as follows: Baseline: 6.36(5.76, 6.96), 6.06(5.23, 6.88) and 6.10(5.32, 6.89); Year 1: 3.94(3.31, 4.58), 4.63(3.84, 5.42) and 3.05(2.50, 3.60); Year 2: 3.70(2.85, 4.56), 5.07 (4.16, 5.97) and 2.96(2.21, 3.71); Year 3: 4.55(3.67, 5.43), 4.82(3.90, 5.74) and 3.96(3.21, 4.71) (Table 2). The p-values reported compare the TNSS area under the curve (AUC) between treatment groups and were calculated using an analysis of covariance (ANCOVA) model at the 0.05 level of significance adjusted for pre-treatment baseline AUC measures. The minimal clinically important difference for this measure within a participant is 1.08. (Table 2). Bottom Panel: A larger change in peak nasal inspiratory flow (PNIF) indicated a higher burden of symptoms during the nasal challenge. Change (litres/minute) was defined relative to the 0 time point in the challenge. Mean (95% Confidence intervals) values for the change in PNIF for sublingual immunotherapy, placebo and subcutaneous immunotherapy groups, respectively, at Baseline and Years 1, 2 and 3 were as follows: Baseline: −110.75(−129.97, −91.54), −121.63(−145.82, −97.43) and −110.62(−136.75, −84.49); Year 1: −80.36(−98.32, −62.41), −123.51(−149.79, −97.22) and −61.05(−76.50, −45.59); Year 2: −70.65(−92.41, −48.89), −128.63 (−159.87, −97.39) and −59.60(−76.66, −42.54); Year 3: −99.71(−122.89, −76.53), −116.59(−144.89, −88.30) and −91.97(−113.97, −69.97). The p-values reported compared the delta PNIF area under the curve (AUC) between treatment groups and were calculated using an analysis of covariance (ANCOVA) model at the 0.05 level of significance adjusted for pre-treatment baseline AUC measures. The minimal clinically important difference for this measure within a subject is 33.9(eTable1).

Figure 3

Time-course of weekly seasonal rhinitis quality of life scores (top panel) and rhinitis severity scores (visual analogue 0–10 cm) during May-July (middle panel). Data are mean weekly values for participants treated with Sublingual immunotherapy (green) Subcutaneous immunotherapy (red), and Placebo (blue) during years 1 and 2 (on treatment) and year 3 (off treatment). The curves in Figure 3 have been smoothed using a cubic spline smoothing function (The cubic spline method uses a set of third-degree polynomials spliced together such that the resulting curve is continuous and smooth at the splices (knot points). The estimation is done by minimizing an objective function that is a combination of the sum of squares error and a penalty for curvature integrated over the curve extent. The p-values reported compare the average values between treatment groups and were calculated using an analysis of covariance (ANCOVA) model at the 0.05 level of significance adjusted for pre-treatment baseline measures. Mini-Rhinoconjunctivitis quality of life questionnaire (mini-RQLQ) and Visual analogue scale (VAS) were analyzed in the modified Intent-to-Treat population comprising: 33 Sublingual immunotherapy participants, 33 Placebo participants, and 34 Subcutaneous immunotherapy participants at year 1; 28 Sublingual immunotherapy participants, 31 Placebo participants, and 30 Subcutaneous immunotherapy participants at year 2; 27 Sublingual immunotherapy participants, 30 Placebo participants, and 29 Subcutaneous immunotherapy participants at year 3. Top Panel: Mini-RQLQ values range from 0–6. Higher RQLQ values reflect subjects who experienced more troublesome nose, eye, and other symptoms effecting regular activities resulting in a lower quality of life. The minimal clinically important difference for this measure within a subject is 0.7(etable 2a). Middle Panel: VAS values range from 0–10 cm. Higher VAS values reflect subjects who experienced worse hay fever symptoms. The minimal clinically important difference for this measure within a subject is 1.0 cm. (etable 2b). Bottom Panel: Average weekly grass pollen counts/cubic meter from a single site in Islington, London, were provided by the Met Office (UK’s national weather service).

Figure 4

Time-course of early (15 min) and late (8 hour) skin responses to intradermal allergen (a, b), changes in serum grass pollen allergen-specific Immunoglobulin E (c), and Immunoglobulin G4 (d). Data are once-yearly mean and 95% confidence intervals for participants treated with Sublingual immunotherapy (green), Subcutaneous immunotherapy (red), and Placebo (blue) at baseline, and years 1 and 2 (on treatment) and year 3 (off treatment). Skin responses were analyzed using ANCOVA with adjustment for baseline values in the modified Intent-To-Treat Population comprising: 33 Sublingual immunotherapy participants, 33 Placebo participants, and 34 Subcutaneous immunotherapy participants at year 1; 31 Sublingual immunotherapy participants, 32 Placebo participants, and 32 Subcutaneous immunotherapy participants at year 2; 30 Sublingual immunotherapy participants, 31 Placebo participants, and 31 Subcutaneous immunotherapy participants at year 3. See etable 4a and etable 4b. Serum allergen-specific Immunoglobulin parameters were analyzed in the Per Protocol Population, comprising 27 Sublingual immunotherapy, 30 Placebo, and 27 Subcutaneous immunotherapy participants at all time points, using a linear mixed model with adjustment for baseline values. Serum allergen-specific Immunoglobulin responses (c and d) were plotted after log transformation for normalization of these variables. The per-protocol sample included participants who were compliant with study medications, defined as taking 50% or more of their study medication for the duration of the study, and who had an assessment of the primary endpoint. All comparisons for skin and serum allergen-specific Immunoglobulin responses between treatment groups at years 1, 2, and 3 have p-values less than 0.01, with the following exceptions: Early skin responses (a) between sublingual immunotherapy and subcutaneous at immunotherapy year 2 and year 3 (p=0.02 and p=0.94 respectfully); Specific Immunoglobulin E (c) between sublingual immunotherapy and placebo at year 2 (p=0.04) and year 3 (p=0.32) and between subcutaneous immunotherapy and placebo at year 1 (p=0.10). See etable 5a and etable 5b.