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Table 1 Summary of the described 300 IR SLIT studies

From: Choosing the optimal dose in sublingual immunotherapy: Rationale for the 300 index of reactivity dose

Study Design and objectives Allergen preparation Population Treatment and enrolled patients Endpoints Main results
SLIT tablets
 5-grass pollen tablet
  Didier et al. [16] Multinational, randomised, DBPC study
Efficacy and safety
5-grass pollen extract (orchard, meadow, perennial rye, sweet vernal, and timothy grasses) Age 18–45 years
Men and women with moderate-to-severe grass pollen-related ARC for ≥2 years, with or without mild asthma
100 IR (n = 157)
300 IR (n = 155)
500 IR (n = 160)
Placebo (n = 156)
RTSSa
Individual symptom scores (sneezing, runny nose, itchy nose, nasal congestion, watery eyes, itchy eyes)
Symptom-free days during the pollen season
Rescue medication use during the pollen season
Quality of life (RQLQ)
Patients’ global evaluation of treatment
Safety
Both the 300 IR and 500 IR doses significantly reduced mean RTSS (3.58 ± 3.0, p = 0.0001; and 3.74 ± 3.1, p = 0.0006, respectively) vs placebo (4.93 ± 3.2)
The score for the 100 IR group was not significantly different from placebo
Analysis of all secondary efficacy variables (sneezing, runny nose, itchy nose, nasal congestion, watery eyes, itchy eyes, rescue medication usage, and quality of life) confirmed the efficacy of the 300 IR and 500 IR doses
No serious side effects were reported
Larsen et al. [31] Single-centre, randomised, DBPC study
Safety
5-grass pollen allergens (orchard, meadow, perennial rye, sweet vernal, and timothy grasses) Age 18–50 years
Men and women with grass pollen-induced AR, with or without mild asthma
Groups 1 and 2: incremental 100 IR, 200 IR, 300 IR, 400 IR and 500 IR SLIT (n = 6) or placebo (n = 4) (Group 1 daily and Group 2 every second day)
Groups 3 and 4: repeated constant 300 IR and 500 IR SLIT, respectively (Group 3: n = 6, Group 4: n = 5) or placebo (Group 3: n = 1, Group 4: n = 2)
AEs, focusing on date of onset, occurrence, duration, intensity, action taken, outcome, and relationship to study drug
Definition and grading of allergic side effects according to WHO
300 IR SLIT (Group 3) administered in a constant dose and incremental doses up to 500 IR (Groups 1 and 2) was generally well tolerated
The majority of AEs were mild to moderate
Most common AEs: oral pruritus, throat irritation, swollen tongue
Severe local AEs (swelling of throat) were observed only for Group 4
No serious systemic AEs were reported
  Malling et al. [32] Multinational, randomised, DBPC study
Efficacy and safety
5-grass pollen extract (orchard, meadow, perennial rye, sweet vernal, and timothy grasses) Age 18–45 years
Men and women with moderate-to-severe grass pollen-induced ARC for at least 2 years, with or without mild asthma
For Group 1 (high specific IgE), Group 2 (high symptom scores), Group 3 (high skin sensitivity) and Group 4 (any of Groups 1, 2 or 3), respectively:
ITT population (n = 569)
100 IR SLIT (n = 55, 61, 34, 105)
300 IR SLIT (n = 59, 47, 32, 100)
500 IR SLIT (n = 57, 60, 39, 103)
Placebo (n = 80, 56, 37, 105)
Safety population (n = 628)
100 IR SLIT (n = 62, 67, 37, 117)
300 IR SLIT (n = 69, 52, 36, 112)
500 IR SLIT (n = 66, 66, 44, 117)
Placebo (n = 82, 59, 40, 112)
ARTSSa
Individual symptom scores
RTSS at the peak of the pollen season
Symptom-free days during the pollen season
Rescue medication use during the pollen season
Quality of life (RQLQ)
Patients’ global evaluation of treatment
Safety
Across the 4 groups, ARTSS (±SD) for 300 IR was 3.91 ± 3.16 (Group 1), 3.83 ± 3.14 (Group 2), 2.55 ± 2.13 (Group 3) and 3.61 ± 2.97 (Group 4)
Group 1: ARTSS did not differ significantly with different doses of SLIT
Groups 2, 3 and 4: 300 IR and 500 IR SLIT doses were significantly more effective than 100 IR and placebo (p ≤ 0.035)
ARTSS was comparable in patients with or without grass-pollen asthma, as well as for mono- or polysensitised patients
All doses of SLIT were considered safe in the patients investigated
  Cox et al. [34] Multicentre, randomised, DBPC, parallel-group study
Efficacy and safety
5-grass pollen allergen extract (orchard, meadow, perennial rye, sweet vernal, timothy) Age 18–65 years
Men and women with documented grass pollen-related ARC for at least 2 previous grass pollen seasons, with or without mild asthma
300 IR (n = 210)
Placebo (n = 228)
DCSa
Daily symptom scores
Symptom-free days during the pollen season
Rescue medication use during the pollen season
Quality of life (RQLQ)
Patients’ global evaluation of treatment
Safety
Mean DCS over the pollen period was significantly lower in the 300 IR group vs the placebo group (LS mean difference: 20.13; 95 % CI: 20.19, 20.06; p = 0.0003; relative reduction: 28.2 %; 95 % CI: 13.0 %, 43.4 %)
300 IR 5-grass pollen SLIT was well tolerated
Most frequently reported AEs: oral pruritus, throat irritation, nasopharyngitis
There were no reports of anaphylaxis
  Wahn et al. [35] Multinational, randomised, DBPC study 5-grass pollen allergen extract (orchard, meadow, perennial rye, sweet vernal, timothy) Age 5–17 years
Male and female children with grass pollen-related moderate-to-severe ARC for at least 2 years, with or without mild asthma
300 IR (n = 131)
Placebo (n = 135)
RTSSa
Individual symptom scores
Rescue medication intake
Safety
RTSS for the 300 IR group was significantly improved by 28.0 % (median improvement 39.3 %) vs placebo (p = 0.001)
Rescue medication use and proportion of days using rescue medication during the pollen season were both significantly reduced in the 300 IR group vs placebo (p = 0.0064 and p = 0.0146)
AEs were generally mild or moderate and in keeping with the known safety profile of SLIT, and no serious side effects were reported
  Didier et al. [36] Multicentre, randomised, DBPC, parallel-group study
Efficacy and safety
5-grass pollen allergen extract (orchard, meadow, perennial rye, sweet vernal, timothy) Age 18–50 years
Men and women with documented grass pollen-related ARC for ≥2 previous grass pollen seasons, with or without mild asthma
300 IR (2 M, administered 2 months prior to start of pollen season) (n = 117)
300 IR (4 M, administered 4 months prior to start of pollen season) (n = 127)
Placebo (n = 133)
DCSa
Individual symptom scores
ACS
Symptom-free days during the pollen season
Rescue medication use during the pollen season
Safety
Patients were treated for 3 consecutive years and followed up for 2 years post-treatment
During the first post-treatment year, a statistically significant decrease vs placebo in LS mean DCS was noted in patients previously receiving active treatment [300 IR (2 M): −31.1 %, p = 0.0019, 300 IR (4 M): −25.3 %, p = 0.0103)
During the second post-treatment year, patients in the 300 IR (4 M) group, but not the 300 IR (2 M) group, showed a statistically significant decrease in LS mean DCS vs placebo (−28.1 %, p = 0.0478)
The significant efficacy in the post-treatment years compared favourably with that during the 3 prior years of active treatment
A statistically significant difference vs placebo was also noted in secondary efficacy measures in both post-treatment years (except for daily RTSS in year 5)
In the absence of any active treatment, the safety profile was similar in the active vs placebo group during either post-treatment year
  Horak et al. [37] Single-centre, randomised, DBPC, parallel-group study 5-grass pollen allergen extract (orchard, meadow, perennial rye, sweet vernal, timothy) Age 18–50 years
Men and women with moderate-to-severe seasonal grass pollen-related ARC for ≥2 previous pollen seasons, with or without mild asthma
300 IR (n = 45)
Placebo (n = 44)
ARTSSa
Nasal airflow, nasal secretion weight and cutaneous reactivity
Safety
A significant treatment effect was achieved after the first (p = 0.0042) and second months (p = 0.0203), which was maintained to the fourth month (p = 0.0007)
In the 300 IR group, mean ARTSS (±SD) decreased at each challenge (week 1: 7.40 ± 2.68, month 1: 5.89 ± 2.43, month 2: 5.09 ± 2.09, month 4: 4.85 ± 2.00)
Mean ARTSS improved by 29.3 % (median: 33.3 %) vs placebo
Most frequent local AEs: oral pruritus, ear pruritus, throat irritation
  Antolin et al. [48] Multicenter, observational, cross sectional study 5-grass pollen allergen extract (orchard, meadow, perennial rye, sweet vernal, timothy) Age ≥6 years
Patients with moderat to severe ARC to grass pollen
591 patients Patients’ HRQoL
Treatment satisfaction
Good level of satisfaction, with an average score of 69.2, on a 0–100 scale (100 being highest satisfaction).
HRQoL questionnaires results were also favourable, mean (SD) scores were 1.40 (1.1) in adults, 1.33 (1.1) in adolescents and 1.15 (1.1) in children, with average scores much closer to 0 (no impairment) than to 6 (severe impairment)
 HDM tablet
  Bergmann et al. 2014 [15] Randomised DBPC study
Efficacy and safety
HDM standardised extract Age 18–50 years
Adults with moderate-to-severe HDM-associated AR for ≥1 year
500 IR (n = 169)
300 IR (n = 170)
Placebo (n = 170)
AAdSSa
Individual symptom score
Rescue medication use
Onset of action
Patients’ global evaluation of treatment
Safety
Both the 500 IR and 300 tablets significantly reduced mean AAdSS vs placebo by −20.2 % (p = 0.0066) and −17.9 % (p = 0.0150), respectively
Efficacy of both doses was maintained during the treatment-free follow-up phase
Onset of action was at 4 months
Participants’ global evaluation of treatment success was significantly higher in the 500 IR and 300 IR groups vs placebo (p = 0.0206 and p = 0.0001, respectively)
AEs were generally application-site reactions, and there were no reports of anaphylaxis
  Okamoto et al. [38] Multicenter randomized, DBPC, parallel-group design
Efficacy and safety
HDM standardised extract Age 12–64 years
Adults with moderate-to-severe HDM-associated AR for ≥2 year
500 IR (n = 296)
300 IR (n = 315)
Placebo (n = 316)
AAdSSa
Physicians’ intranasal examination
Quality of life
Patients’ global evaluation of treatment
Safety
Both the 500 IR and 300 tablets significantly reduced mean AAdSS vs placebo by −13.12 % (p < 0.001) and −18.2 % (p < 0.001), respectively
Both nasal mucosal swelling and rhinorrhea were markedly and significantly improved in both active treatment groups.
In the Japanese RQLQall 3 domains showed a statistically significant improvement difference in the 300 IR group compared to placebo.
Participants’ global evaluation of treatment success was significantly higher in the 500 IR and 300 IR groups vs placebo (p = 0.0002 and p < 0.0001, respectively)
AEs were generally application-site reactions, and there were no reports of anaphylaxis
  Ferrés et al. [39] Retrospective, observational, single-centre study
Efficacy and safety
HDM standardised extract Age 6–18 years
Patients with AR who were mono-sensitised to HDM, with or without mild asthma
300 IR (n = 78) Global assessment of SLIT efficacy measured using a VASa
Rhinitis medication consumption score
Global asthma score
Safety
Significant improvement in allergy severity at 6 months vs baseline (7.3 ± 4.6 vs 4.0 ± 1.7 cm on the VAS, respectively; p < 0.001), which was maintained throughout the 4-year follow-up period
Symptomatic medication use was significantly reduced in the first 6 months vs baseline (0.8 ± 1.6 points vs 4.6 ± 2.5 points, respectively; p < 0.001) and remained very low until the end of follow-up
SLIT was well tolerated, and no anaphylactic or life-threatening reactions were reported
SLIT drops
 5-grass pollen drops
  Ott et al. [17] Randomised, DBPC, parallel-group, multicentre study
Efficacy and safety
5-grass pollen extract (orchard, meadow, perennial rye, sweet vernal, and timothy grasses) Age 7.9–64.7 years
Men and women with grass pollen-related ARC using symptomatic medication during the grass pollen season, with or without mild asthma
300 IR (n = 99)
Placebo (n = 46)
Combined symptom and rescue medication scorea
Individual symptom scores
Safety
Median combined scores decreased by 44.7 % in the SLIT group and 14.7 % in the placebo group vs baseline, by the third pollen season (p = 0.0019)
Similar changes were observed for symptom scores, with a successive decrease of 39.7 % (SLIT) and fluctuations between +13.6 and −1.5 % for placebo (p < 0.05) over the 3 pollen seasons
Combined score (p = 0.0508) and symptom score improvements (p = 0.0144) with SLIT continued during follow-up
SLIT was well tolerated, and no serious systemic or anaphylactic reactions were reported
 Birch pollen drops
  Worm et al. [19] Randomized, DBPC, multicentre study
Efficacy and safety
Birch pollen allergen standardised extract Age 18–65 years
Men and women with birch pollen-related ARC for ≥2 previous birch pollen seasons that required intake of symptomatic treatments, with or without OAS, with or without mild asthma
300 IR (n = 283)
Placebo (n = 289)
AAdSS over the second pollen seasona
AAdSS over the first pollen season
Individual symptom scores
Rescue medication use during the pollen season
Quality of life (RQLQ)
Safety
LS mean AAdSS was significantly lower in the 300 IR group than in the placebo group (LS mean difference -2.04, 95 % CI [−2.69, −1.40], (p < 0.0001) over the second pollen season (relative reduction of 30.6 %)
Improvements in AAdSS were similar in patients with and without OAS (relative LS mean differences of −33.6 and −28.4 %, respectively)
A significant reduction in LS mean AAdSS was also observed over the first pollen season
SLIT was well tolerated, and no anaphylaxis was reported
Most frequently reported AEs: application-site reactions (oral pruritus), throat irritation, mouth edema
 Grass and tree pollen drops
  Seidenberg et al. 2009 [44] Large observational study
Safety
5-grass pollen (cocksfoot, meadow, rye, sweet vernal, and timothy grasses) or tree pollen (birch, alder, and hazel) allergen standardised extract Age 5–17 years
Children and adolescents with AR for ≥1 year due to grass or tree pollen, with or without mild to moderate asthma
Ultrarush titration high-dose 300 IR SLIT (n = 193) Frequency and intensity (mild, moderate, severe) of expected local, gastrointestinal, and generalised AEsa
Patients’ and investigators’ global assessment of tolerability
Ultrarush titration was well tolerated
During ultrarush titration, 60 patients (31 %) reported 117 predominantly mild and local AEs, which resolved within 150 min
During the maintenance phase, 562 AEs were reported
Most frequently reported local events: oral pruritus, burning sensation, lip or tongue swelling, gastrointestinal symptoms
Most frequently reported systemic events: rhinoconjunctivitis, asthma
There was 1 clinically significant asthma event in an 11-year old boy with known asthma, who resumed SLIT after 4 days
 HDM drops
  Wang et al. [18] DBPC, randomised study
Efficacy and safety
HDM standardised extract Age 14–50 years
Patients with mild or moderate, persistent, HDM-induced asthma for ≥1 year
300 IR (n = 308)
Placebo (n = 157)
Well-controlled asthma for ≥16 of the last 20 weeks of treatmenta
Totally controlled asthma
Safety
Well-controlled asthma was achieved by 85.4 and 81.5 % of patients in the 300 IR and placebo groups, respectively (p = 0.244)
Post hoc analysis by asthma severity found significant clinical benefits in actively treated subjects with moderate asthma at baseline (n = 175), but not those with mild asthma:
Greater achievement of well-controlled asthma (300 IR: 80.5 %, placebo: 66.1 %; p = 0.021) and totally controlled asthma (300 IR: 54.0 %, placebo: 33.9 %; p = 0.008)
Higher percentage of patients with an asthma control questionnaire score <0.75 (300 IR: 56.6 %, placebo: 40.0 %; p = 0.039)
Greater mean reduction in inhaled corticosteroid use (300 IR: 218.5 μg, placebo: 126.2 μg; p = 0.004)
300 IR was well tolerated, and no treatment-related serious AEs were reported
  Trebuchon et al. [46, 47] Retropsective, multicenter, observational study HDM standardised extract Age ≥5 years
Children and adults with respiratory allergy and proven sensitization to HDM
1289 patients Physician perception of patient satisfaction
Compliance with treatment
Over 84 % of adult and pediatric patients with AR (with or without asthma) were satisfied and adhered to their treatment
 Grass and tree pollen, and HDM drops
  Corzo et al. 2012 [45] Multicentre, observational, epidemiological study
Safety
5-grass pollen, olive tree pollen or HDM standardised extracts Age 5–15 years
Children and adolescents with AR, ARC and/or bronchial asthma due to grass pollen, olive pollen and/or HDM
300 IR (n = 74) Tolerability and occurrence of local oral, systemic and gastrointestinal AEsa After the first administration, 22 % of children had self-limiting pruritus, 4 % had moderate OAS (intense oropharyngeal itching) and 1 patient had diffuse abdominal pain
No systemic reactions were recorded
No patients reported problems during the maintenance phase, and there were no discontinuations of therapy
  1. AAdSS Average Adjusted Symptom Score, ACS Average Combined Score, AE adverse event, AR allergic rhinitis, ARC allergic rhinoconjunctivitis, ARTSS Average Rhinoconjunctivitis Total Symptom Score, CI confidence interval, DBPC double-blind, placebo-controlled, DCS Daily Combined Score, HDM house dust mite, IR index of reactivity, LS least squares, OAS oral allergy syndrome, RQLQ Rhinoconjunctivitis Quality of Life Questionnaire, RTSS Rhinoconjunctivitis Total Symptom Score, SD standard deviation, SLIT sublingual immunotherapy, VAS visual analogue scale, WHO World Health Organization
  2. aDenotes primary outcome measure