How does the efficacy and safety of Oralair^® compare to other products on the market?

Figures & data

Table 2 Quality of evidence (according to the GRADE approach) of SLIT studies on Oralair^®, and several pivotal trials with other grass pollen formulations

Author, year study details	Design (starting score)	Large effect**	Confound annulated*	Dose–response gradient	Total (+)	Limitations in design/execution	Inconsistency of results	Indirectness of evidence	Imprecision of results	Publication bias	Total (−)	Quality of evidence
Oralair^® for allergic rhinoconjunctivitis trials
Didier et al,^Citation19 2007 SAR (10% mild asthma) 157 100IR/d, 155 300IR/d, 160 500IR/d, 156 placebo Pre (4 m) + coseason, 300IR −25 μg group 5 daily	DBPC (4)	X	X	Yes	+1	Symptom score alone is the primary outcome variable	X	X	X	X	−1	4, high
Didier et al,^Citation20 2011 SAR (13.7% mild asthma) SLIT preseason (2 m) + coseason: 207 recruited, 147 FAS SLIT preseason (4 m) + coseason: 207 recruited, 149 FAS Placebo 219 recruited, 165 FAS 25 μg group 5-grass tablet/day	DBPC (4)	X	Novel adjusted symptom score previously validated	Trend to more improvement compared to placebo year by year (NS)	+1.5	ITT but data of 59 pts not apt for inclusion, −1	X	No medication score (primary outcome −novel symptom score adjusted for medication intake)	X	X	−1	3–4, moderate–high
Didier et al,^Citation15 2013 Continuation of Didier et al 2011^Citation20 +1 yr SAR (13.7% mild asthma) After 3 yrs SLIT and 1 yr observation: SLIT preseason (2 m) + coseason: 137 SLIT preseason (4 m) + coseason: 143 Placebo 155	DBPC (4)	X	X	X	0	Dropout rate >15%	Reduction in days with rescue med in 300IR but not in 500IR	X	X	X	−1	3, moderate
Didier et al,^Citation16 2015 Continuation of Didier 2011^Citation20 +2 yrs SAR (12.7% mild asthma) After 3 yrs SLIT and 2 yrs observation: SLIT preseason (2 m) + coseason: 117 SLIT preseason (4 m) + coseason: 127 Placebo 133	DBPC (4)	X	Large symptom reduction in placebo (more severe pts withdrew), even so statistically significant improvement in SLIT grps	X	+1	Post hoc calculation of combined symptom–medication score, but enough power to do so Dropout since start of study: AIT 41%, placebo 39%	X	X	X	X	−2	3, moderate
Wahn et al,^Citation21 2009 SAR (21% mild asthma) 131 SLIT, 135 placebo; 4–17 yrs of age precoseason, 25 μg group 5-grass tablet/d	DBPC (4)	X	X	X	0	X	X	X	X	X	0	4, high
Halken et al,^Citation22,¥ 2010 Moderate-severe AR (intermit asthma) SLIT 131, placebo 135, 5–17 yrs of age 25 μg group 5 daily, precoseason 6 m	DBPC (4)	+1	X	X	+1	No description of dropouts	X	X	Large CI	X	−2	3, moderate
Horak et al,^Citation23 2009 Onset of action: allergen challenge chamber ARC, 18–49 yrs of age SLIT 45, placebo 44 25 μg group 5-daily for 4 m; out of season	DBPC (4)	4 m: +1	X	Trend for dose–effect over time	+1	Blinding and randomization technique not explained	No change in nasal airflow and nasal secretion weight	X	X	X	−2	3, moderate
Cox et al,^Citation5 2012 ARC (20% mild asthma) SLIT 210, placebo 228 precoseason, 25 μg group 5-grass tablet/d	DBPC (4)	X	X	X	0	X	X	X	X	X	0	4, high
Other grass pollen sublingual tablet immunotherapy trials
Durham et al,^Citation24 2006 AR (and mild persist asthma), 18–65 yrs of age Pre-(8-week) coseasonal for one season SLIT 2500SQ-T 144, 25000SQ-T 148, 75000SQ-T 321, placebo 307 0.5, 5, or 15 μg Phl p 5 daily	DBPC (4)	X	X	Yes	+1	X (GOOD: ITT analysis)	X	X	Differences vs placebo and trends calculated, not between dosing grps	X	−1	4, high
Dahl et al,^Citation25 2008 AR (and mild persist asthma), 18–65 yrs of age Continuous, 22 m Second year: SLIT 189, placebo 162 15 μg Phl p 5 daily	DBPC (4)	X	X	X	0	Originally plannedas 1 yr trial. Only 60%/51% of original AIT/placebo continued. NS difference insymptom–medication scores between continuing/stop: −0.5	X	X	X	X	−0.5	3–4, moderate–high
Durham et al,^Citation17 2012 AR (and mild persist asthma), 18–65 yrs of age Continuous, 34 m Fifth year: SLIT 135, placebo 103 15 μg Phl p 5 daily	DBPC (4)	X	X	X	0	Same as earlier: −0.5+ dropout rate sincestudy extension: 18.6% AIT and 36%placebo: −1	X	X	X	X	−1.5	2–3, low–moderate
Nieminen et al,^Citation26 2010 (mechanistic study) Respiratory allergy, 5–15 yrs of age SLIT low dose 10, high 10, placebo 10 Low: 24.000 SQ-U, high 200.000 SQ-U/week, 2 yrs	DBPC (4)	X	X	Yes	+1	X	X	X	Small grps	X	−1	4, high
Bufe et al,^Citation27 2009 SAR (42% mild asthma) 114 SLIT, 120 placebo; 5–16 yrs of age	DBPC (4) Rhinitis	X	X	X	0	X	X	X	X	X	0	4, high
Precoseason, 15 μg Phl p 5 tablet/d	DBPC (4) Asthma	X	X	X	0	X	X	Only symptom + medication	Very small numbers (9 vs 3 days)	X	−2	2, low
Blaiss et al,^Citation28 2011 AR (and mild persist asthma), 5–17 yrs of age Precoseasonal for one season SLIT 175, placebo 169 15 μg Phl p 5 daily	DBPC (4)	X	X	X	0	X(GOOD: ITTanalysis)	X	X	X	X	0	4, high
Nelson et al,^Citation29 2011 ARC (24% mild asthma), 18–65 yrs of age SLIT 184, placebo 207 15 μg Phl p 5 daily, 6 m precoseason	DBPC (4)	X	X	X	0	X	X	X	X	X	0	4, high
Maloney et al,^Citation30 2014 ARC (25% mild asthma), 5–65 yrs of age SLIT 750, placebo 751 Precoseason, 15 μg Phl p 5 tablet/d	DBPC (4)	X	X	X	0	X (GOOD: ITTanalysis)	X	X	X	X	0	4, high
Some of the most recent grass pollen sublingual liquid immunotherapy trials
Bozek et al,^Citation31 2014 SAR, 60–70 yrs of age SLIT 41, placebo 37 20 μg group 5 (240IR) drops 5 days/wk 4 m preseasonal for 3 years	DBPC (4)	X	X	X	0	No clear description randomization	X	X	Non-validated VAS scoring for symptoms	Medication scores 1st and 2nd year not stated	−2.5	1–2, (very) low
Swamy et al,^Citation32 2012 AR (mild/moderate persist asthma), 6–57 yrs of age (55% of SLIT grp are children) Dual SLIT 20, placebo 10 15 μg Phl p 1 (sic) and 20 μg Der f 1+2, daily for 12 months. Post-Tx evaluations 12+6 and 12+12 m	DBPC (4)	X	Small grps and even so statistically significant difference	X	+1	Randomizationmethod notdescribed, −1	X	X	Small grps	X	−2	3, moderate
Wahn et al,^Citation33 2012 ARC (and GINA gr I–II asthma), 4–12 yrs of age Precoseasonal SLIT, placebo 40 μg group 5 drops daily, 8 m	DBPC (4)	X	X	X	0	No ITT mentioned, −1. 16.5% dropout in active grp, −,20%	X	X	(change in lung symptoms not reported)	X	−1 (for RC)	3 (for RC)
Stelmach et al,^Citation34 2012 Rhinitis (20 also asthma), 6–18 yrs of age Precoseasonal 20 pts, continuous 20 pts, placebo 20 pts, for 2 yrs 10 μg group 5-grass drops daily	DBPC (4)	X	X	X	0	(preestablished adjusted to 1,000 pollen grains/m^3 of symptom and medication scores: no reduction)	X	X	Small grps, underpowered	X	−1	3, moderate
Panzner et al,^Citation35 2011 (24 m open continuation of 12 m DBPC^Citation36) AR, mean age 17.6 yrs (±10 yrs), nr of children unknown 3 yrs study continuation after 1 yrs DBPC SLIT 26, supralingual 25 pts 11.2 μg group 5 (six-grass pollen extract) 3/week for 3 yrs	Randomized, noncontrolled (4)	X	X	Year-by-year improvement in symptons and medications, +1	+1	No control grp, small grps: only statistically significant difference pre-post Tx, not between both active grps; no description dropout per grp	X	Post hoc fusion of grps to improve stats, but does not seem to affect outcomes; −0.5	X	Incorrect conclusion: medication score in supra-lingual not improved	SLIT −2.5; supra-lingual −3.5	SLIT: 2.5 supra-lingual 1.5
Ott^Citation15 2009 Persistent seasonal AR, 8–65 yrs of age SLIT 99, placebo 46 five-grass, 25 μg group 5-grass drops daily (300IR) coseasonal ×3 yrs	DBPC (4)	X	X	X	0	Methods of randomization nor blinding described: −1 Statistically significant difference grps at baseline: −1	X	X	Median scores not mean	X	−3	1, very low
Agostinis et al,^Citation37 2009 AR (60% mild asthma), 4–16 yrs of age SLIT 20, control 20 precoseasonal for 2 yrs 1,000 AU drops five × week	Randomized controlled (4)	X	Small grps, even so statistically significant	X	+1	No medication score	X	VAS “well-being” only once a year: −2	X	X	−3	2, low
Ahmadiafshar et al,^Citation38 2012 ARC, 5–18 yrs of age SLIT 12, placebo 12 pts 900IR Lolium drops, 3 times/wk, 6 m	Randomized controlled (4)	X	X	X	0	Very small grps. No comparison of symptom–medication reduction SLIT vs placebo	Much more adverse effects in placebo grp	Incomplete nasal symptom score (no congestion measured)	No SD nor CI given for symptom nor medication	X	−4	0, very low
Pivotal grass pollen subcutaneous immunotherapy trials
Frew et al,^Citation39 2006	DBPC	X	X	+1	+1	X	X	X	X	X	0	4+, high
Walker et al,^Citation40 2001	DBPC	X	X	X	0	X	X	X	X	X	0	4, high
Durham et al,^Citation41 1999	DBPC	X	X	X	0	X	X	X	X	X	0	4, high
Dolz et al,^Citation42 1996	DBPC	X	X	+1, progressive improvement over the 3 yrs	+1	−1, no clear primary end-point, no comparison A vs P	X	X	−1, P-values: not clear if over time or comparison A vs P	X	−2	3, moderate
Leynadier et al,^Citation43 2001	DBPC	X	X	X	0	−1, small grps	X	X	X	X	−1	3, moderate

Notes:

* All plausible confounding variables may be working to reduce the demonstrated effect, or increase the effect if no effect was observed.

** RR − relative risk. Large effect RR <0.5, very large effect RR <0.2. RR has been calculated from the data given in the articles.

¥ Same study as Wahn 2009.¹⁶

Abbreviations: A, active; P, placebo; PAR, perennial allergic rhinitis; pt, patient; SAR, seasonal allergic rhinitis; SLIT, sublingual immunotherapy; DBPC, double-blind, placebo-controlled; SPT, skin prick test; yrs, years; m, months; FAS, full analysis set; vs, versus; GRADE, Grading of Recommendations Assessment, Development and Evaluation; AIT, allergen immunotherapy; NS, not significant; ITT, intention to treat; Med, medication; AR, allergic rhinitis; CI, confidence interval; ARC, allergi rhinoconjunctivitis; SQ-T, standard quality tablets; VAS, visual analog scale; Post-Tx, post treatment; GINA, Global Initiative on Asthma; RC, rhinoconjunctivitis; Nr, number; SD, standard deviation; SQ-U’ standard quality unit; Grp, group; WAO, world allergy organization.

Table 1 Number and quality according to GRADE of the double-blind, placebo-controlled, randomized trials of SC-AIT in patients with SAR included in the Cochrane meta-analysis 2007

Author	Year	Country	ITx	Plac	Quality score**
Alvarez-Cuesta	2005	Spain	25	28	3, moderate
Ariano	1999	Italy	13	12	2, low
Armentia-Medina	1989	Spain	19	11
Arvidsson	2002	Sweden	24	25	3, moderate
Balda*	1998	Germany	51	60	2, low
Bodtger*	2002	Denmark	17	18	3–4, moderate–high
Bousquet	1987a	Germany/France	15	19
Bousquet	1987b	France	39	20
Bousquet	1988	Germany/France	15	10
Bousquet	1989	Germany/France	13/15/18	14
Bousquet*	1990	France	20/19	18
Bousquet	1991	Germany/France	18/17	18
Brewxzynski*	1999	Germany	10	10
Brunet	1992	Canada	13	14
Corrigan*	2005	UK/Germany	77	77	2–3, low–moderate
Dolz	1996	Spain	18	10	3, moderate
Drachenberg*	2001	German/Austria	74	50	4, high
Drachenberg	2002	Germany	54	27	Not scored
Ferrer*	2005	Spain	28	29	3, moderate
Fling	1989	USA	12	7
Frew*	2006	UK	203	103	4+, high
Grammer	1982	USA	21	19
Grammer	1983	USA	13	13
Grammer	1984	USA	21	21
Grammer	1984	USA	19	31
Grammer	1986	USA	15, 4, 1	20
Grammer	1987	USA	36	37
Iliopoulos	1991	USA	21	20
Jutel*	2005	Poland/Germany	29	28	2, low
Karmaker	1994	India	86	19
Lee	1982	USA	48	28
Leynadier	2001	France	16	13	3, moderate
Litwin	1991	USA	20	19
Meriney*	1986	USA	10	10
Metzger	1981	USA/England	50	50
Mirone	2004	Italy	16	16	1–2, very low
Norman	1982	USA	10	10
Ortolani*	1984	Italy/USA	8	7
Ortolani*	1994	Italy	18	17
Paraskevopoulos	2005	UK	12	6
Pastorello	1992	Italy/Germany	10	9
Tari	1997	Italy/Germany	20	20	2, low
Varney*	1991	UK	21	19
Walker*	2001	UK	22	22	4, high
Zenner*	1997	Germany	45	42	4, high

Notes:

* Studies used for the symptom score of Cochrane meta-analysis 2007.¹

** GRADE score is the scoring of quality of evidence according to GRADE as reported in online documents;² only publications from 1995 onward were scored. Data in bold indicate studies used for the dosing recommendation of grass-pollen SC-AIT in the practice parameters on immunotherapy, third update.³

Abbreviations: AIT, allergen immunotherapy; GRADE, Grading of Recommendations Assessment, Development and Evaluation; SAR, seasonal allergic rhinitis; SC-AIT, subcutaneous allergen immunotherapy; ITx, immunotherapy; Plac, placebo.

Table 3 Clinical efficacy of SLIT: focus on five-grass tablet Oralair^®

Author, year	Q score*	Age (yr)	Active/placebo or control	Dropout	Allergen, drop/tablet	Duration	Dose (µg/dose and dosing frequency)	Dose vs SCIT	Disease	Manufacturer	Statistically significant differences found in the following comparisons	No statistically significant differences in following comparisons
Oralair^®
Didier et al^Citation19 2007	4	18–45	157-155-160/156	18-22-19/10	5-grass, tablet	4–6 m	100, 300 and 500IR daily (300IR −25 μg Phl p 5)	30	R(mA)	Stal	SLIT vs placebo: ⬇ Total rhinoconjunctivitis symptom score, days without symptoms in 300IR and 500IR groups. ⬇ Days with rescue medication use in 300IR group. ⬆ QoL dose-dependent increase in sIgG4	SLIT vs placebo: NS differences 100IR in any variable NS days with rescue medication use in 500IR group vs placebo
Didier et al^Citation20 2011	3–4	18–50	2 m preseason 207/4 m preseason 207/placebo 219	60/58/54	5-grass, tablet	4–6 m ×3 yrs	25 μg Phl p 5 daily (300IR)	30	R(mA)	Stal	SLIT vs placebo: ⬇ Average adjusted sympt score in 2 m and 4 m preseasonal groups, and ⬇ Daily combined and medication score	X
Didier et al^Citation15 2013	2–3			At 4 yrs: 70/65/64							SLIT vs placebo: ⬇ Average adjusted symptom score in 2 m and 4 m preseasonal groups. ⬇ Daily combined and medication score	X
Didier et al^Citation16 2015	3			At 5 yrs: 90/80/86							SLIT vs placebo: after 3 yrs SLIT: ⬇ Daily combined score in 2 m and 4 m preseasonal group. After 2 yrs post-SLIT: ⬇ Daily combined score in 4 m preseasonal group	2 yrs after treatment: in 2 m preseasonal: daily combined score, daily rhinitis and daily med score In 4 m preseasonal: daily rhinitis score
Wahn et al^Citation21 2009	4	4–17	139/139	8/4	5-grass, tablet	8 m	25 μg Phl p 5 daily (300IR)	30	R(mA)	Stal	SLIT vs placebo: improved total and individual rhinitis sympt (P−0.01) and medication (P−0.0064) scores. Less days with medication intake (P−0.015)	X
Halken et al^Citation22 2010 (additional data to Wahn et al^Citation21 2009)	3					6–8 m	25 μg Phl p 5 daily (300IR)	30	R(mA)	Stal	SLIT-placebo: total symptom score reduced at whole and peak pollen season. Nasal and ocular sympt reduced. Less rescue medication during whole and peak pollen season	X
Horak et al^Citation23 2009	3	18–50	45/44	3/3	5-grass, tablet	4 m	25 μg Phl p 5 daily (300IR)	30	RC(mA)		SLIT vs placebo: allergen challenge chamber (ACC) symptom reduction at 1, 2, and 4 months	SLIT vs placebo: ACC symptom reduction at 1 week; ACC nasal airflow and weight of nasal secretions and SPT reactivity at 1, 2, and 4 months
Cox et al^Citation45 2012	4	18–65	210/228		5-grass, tablet	6 m	25 μg Phl p 5 daily (300IR)	30	ARC	Stal	SLIT-placebo: whole pollen season daily combined (− sympt + med), sympt, medication and adjusted symptom scores all reduced in SLIT. RQLQ and patient rating of treatment efficacy better in SLIT	SLIT-placebo: nasal itching
Other grass pollen SL-AIT
Maloney et al^Citation30 2014	4	5–65	750/751			6 m	15 μg Phl p 5 daily	NS	RC(A)	ALK	SLIT-placebo: whole pollen season daily total combined (TCS − sympt+ med), sympt and medication scores all reduced in SLIT. Peak pollen TCS and RQLQ better in SLIT	X
Blaiss et al^Citation28 2011	4	5–17	175/169	33/29	Phleum pratense, tablet	6 m	15 μg Phl p 5 daily	NS	RC(A)	ALK	Active vs placebo: daily symptom (25%), daily med (81%), total score (26%) and QoL improved 18% (P<0.04)	SLIT-placebo: asthma symptom score
Bufe et al^Citation27 2009	4	5–16	126/127	12/7	Phleum pratense, tablet	6 m	15 μg Phl p 5 daily	30	R(mA)	ALK	Active vs placebo: sign reduction in RC symptoms score (−24%), asthma score (−64%), RC meds (−34%), well days (+28%). All P<0.03	X
Durham et al^Citation24 2006	4	18–65	75k: 321 25k: 148 2.5k: 144 plac: 307	75k: 27 25k: 9 2.5k: 8 plac: 21	Phleum pratense, tablet	4 m	15 μg Phl p 5 daily	30	RC(mA)	ALK	Active 75,000 SQ-T vs placebo: ⬇ Medication score entire season, sympt and med score peak pollen season and subgroup with ≥2 m pre-seasonal SLIT. ⬆ QoL and well days	75.000 SQ-T vs placebo: sympt score over entire season 2.500 and 25.000 SQ-T NS in any variable
Durham et al^Citation17 2012	2–3	18–65	316/318	5 years: 181/215	Phleum pratense, tablet	34 m	15 μg Phl p 5 daily	30	RC(mA)	ALK	Active vs placebo: ⬇ Medication score entire season, sympt and med score peak pollen season and subgroup with ≥2 m preseasonal SLIT. ⬆ QoL and well days
Bozek et al^Citation31 2014	2	60–70	41/37	3/3	5-grass, liquid	4 m for 3 yrs	20 μg group 5 5 days/week	NS	RC	Stal	Active vs placebo: sign. ⬇ total nasal symptom score in active 1st, 2nd, and 3rd season (3rd yrs: 64 vs 7%). ⬇ Med score 3rd year 51% more than placebo. No SAE, only transient local AE in active group. Less NPT nasal flow reduction	Active vs placebo: non-nasal symptoms, PEF, NPT symptom score, sIgE [Medication scores 1st and 2nd year?]
Stelmach et al^Citation34 2012	4 3	6–18	Cont 20 Pre-co 20 Pla 20	1/3/2	Grass, drops	2 yrs	10 μg group 5 daily cont: for 2 yrs Pre-co: 2×6 mo	NS	RC(mA)	Stal	Both active groups vs placebo: sign improvement Med + Symp score, sympt score Pre-co group vs placebo: sign reduction Med score X	X Medication score continuous group. Asthma symptoms
Swamy et al^Citation32 2012	3	5–58	20/10	0/0	DUAL − grass and HDM, drops	12 m	15 μg Phl p 1	1–2.8× each dose	RC	Greer	Active-placebo: Rhinoconjunctivitis symptom score, medication score and combined score reduced at 12 m and at 24 m (12 m after treatment discontinuation) (P<0.001)	X
Wahn et al^Citation33 2012	3	4–12	158/plac 49	26/2	6-grass, drops	8 m	40 μg group 5 daily	NS	RC(A)	All pharm	SLIT vs placebo: change in pre-posttreatment higher for Symp-Med, Symp, Med scores. SLIT higher rate of positive response (−.40% decrease of the AUC of the SMS)	SLIT vs placebo: Mean nr. of well days
Pajno et al^Citation46 2011	3	8–16	Continuous 40/coseasonal 40	3/5	Grass, drops	CONT 3 yrs COS: 3×4 m	8 μg group 5, 5 times/week	NS	RA	Stal	Continous vs coseasonal: 1st year: sympt + med, symp, chest sympt and Med scores improved more in CONT SLIT	3rd year: no difference in clinical outcomes between continuous vs co-seasonal SLIT
Panzner et al^Citation35 2011open extension ofprevious DBPC 12 mtrial (Panzner et al^Citation36 2008)	2.5	Mean 17.6	SLIT 26, supra-lingual 25	8	6-grass, drops	12 m (+24 m open)	11.2 μg group 5, 3 times/week	Total: 20×	R	Sevapharma	Pre-posttreatment Supra and SLIT: sympt, medication and combined score reduced year by year	SLIT vs Supra: trend for more sympt and med reduction in SLIT (NS)
Ott et al^Citation44 2009	1	8–68	142/67	43/21	5-grass, drops	3 m ×3 yrs	25 μg Phl p 5 daily (300IR)	30	R	Stal	SLIT vs placebo improvement vs baseline year: ⬇ combined symptom-med score progressively over 3 treatment years (P−0.043–0.0019)	SLIT vs placebo compared to baseline year: SLIT higher medication score (!)1y post-Tx: combined sympt-med score NS
Agostinis et al^Citation37 2009		4–16	SLIT 20, control 20	0/0	Grass, tablet	pre-co for 2 yrs	1000 AU drops 5× week	NS	R(A)	Lofarma	SLIT vs control: VAS improved after 1st and 2nd year (both: P<0.05). SLIT pre-post Tx: reduction in sympt (P<0.05)	Control pre-post Tx: no reduction in sympt
Ahmadiafshar et al^Citation38 2012	0	5–18	SLIT 12, Plac 12	2/2	Lolium, drops	6 m	900IR 3/week	100?	RC	Stal	SLIT pre-post Tx: reduction in sympt (P<0.05) and medication score (P<0.05)	SLIT vs placebo: not reported
Stelmach et al^Citation47 2009	2	6–17	SLIT 20, plac 15	5/10	Grass, drops	pre-co for 2 yrs	10 μg group 5 grass drops daily	NS	A	Stal	SLIT vs Pl: asthma symptoms (P<0.002), nasal sympt (P<0.04), nasal + asthma sympt, asthma medication and nasal + asthma + med score. (both P<0.001)	SLIT vs Pl: ocular symptoms, total asthma + nose + eye sympt
Trials with onlysafety data
Seidenberg et al^Citation48 2009	1	5–17	SLIT 193	10 (+50 <4 m treatment)	Grass and/or tree, drops	4 m	Started with ultra-rush up-dosing: 30-90-150-300IR each 30 minutes (μg?)	Final dose approx 30× SCIT dose	RC(A)	Stal	During updosing: 60 pts (31%) reported 117 predominantly mild and local AE, which resolved within 150 minutes During maintenance: 562 AE; most frequent local AE were oral pruritus, burning sensation, lip or tongue swelling, and GI symptoms; the most frequent systemic AE were RC and A. One clinically significant asthma event in an 11-year old male asthmatic: SLIT was resumed after 4 days

Notes:

* Q score − quality assessment according to GRADE. Ref for effect size calculation: Thalheimer W, & Cook S. (2002, August). How to calculate effect sizes from published research articles: A simplified methodology. Retrieved November 16, 2012 from http://work-learning.com/effect_sizes.htm. X values represent trials where there were no parameters of importance to report in the corresponding column. Reproduced from Annals Allergy Asthma Immunol. Epub 2016. Larenas-Linnemann D, Why direct efficacy comparison of SLIT tablets for rhino-conjunctivitis, based on existing data, is non-valid. Copyright © 2016 with permission from Elsevier.⁶¹

Abbreviations: A, asthma; mA, mild asthma; AUC, area under the curve; B2, beta2-agonist; CET, cetirizine; DBPC, double-blind placebo-controlled; GI, gastrointestinal; HDM, house dust mite; ICS, inhaled corticosteroid; Med score, medication scores; MEF25, mid expiratory flow at 25% pulmonary capacity; NS, not stated or not applicable; OIT-low/high, oral immunotherapy low dose/high dose; PFT, pulmonary function testing; QoL, quality of life; R, rhinitis; RC, rhinoconjunctivitis; SAE, serious adverse event; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy; CONT SLIT, continuous year round schedule of SLIT; yrs, years; m, months; SMS, symptom and medication score; Stal, Stallergens; Tx, treatment.

DidierAMallingHJWormMOptimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitisJ Allergy Clin Immunol200712061338134517935764

 PubMed Web of Science ®Google Scholar

DidierAWormMHorakFSustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitisJ Allergy Clin Immunol2011128355956621802126

 PubMed Web of Science ®Google Scholar

DidierAMallingHJWormMPost-treatment efficacy of discontinuous treatment with 300IR 5-grass pollen sublingual tablet in adults with grass pollen-induced allergic rhinoconjunctivitisClin Exp Allergy201343556857723600548

 PubMed Web of Science ®Google Scholar

DidierAMallingHJWormMHorakFSussmanGLProlonged efficacy of the 300IR 5-grass pollen tablet up to 2 years after treatment cessation, as measured by a recommended daily combined scoreClin Transl Allergy201551226097680

 PubMed Web of Science ®Google Scholar

WahnUTabarAKunaPEfficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitisJ Allergy Clin Immunol2009123116016619046761

 PubMed Web of Science ®Google Scholar

HalkenSAgertoftLSeidenbergJFive-grass pollen 300IR SLIT tablets: efficacy and safety in children and adolescentsPediatr Allergy Immunol201021697097620718927

 PubMed Web of Science ®Google Scholar

HorakFZieglmayerPZieglmayerREarly onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamberJ Allergy Clin Immunol2009124347147719647862

 PubMed Web of Science ®Google Scholar

CanonicaGWCoxLPawankarRSublingual immunotherapy: World Allergy Organization position paper 2013 updateWorld Allergy Organ J201471624679069

 PubMedGoogle Scholar

DurhamSRYangWHPedersenMRJohansenNRakSSublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitisJ Allergy Clin Immunol2006117480280916630937

 PubMed Web of Science ®Google Scholar

DahlRKappAColomboGSublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 yearsJ Allergy Clin Immunol2008121251251818155284

 PubMed Web of Science ®Google Scholar

DurhamSREmmingerWKappASQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trialJ Allergy Clin Immunol2012129371772522285278

 PubMed Web of Science ®Google Scholar

NieminenKValovirtaESavolainenJClinical outcome and IL-17, IL-23, IL-27 and FOXP3 expression in peripheral blood mononuclear cells of pollen-allergic children during sublingual immunotherapyPediatr Allergy Immunol2010211 Pt 2e174e18419566585

 PubMed Web of Science ®Google Scholar

BufeAEberlePFranke-BeckmannESafety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapyJ Allergy Clin Immunol2009123116717319130937

 PubMed Web of Science ®Google Scholar

BlaissMMaloneyJNolteHGawchikSYaoRSkonerDPEfficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescentsJ Allergy Clin Immunol20111271647121211642

 PubMed Web of Science ®Google Scholar

NelsonHSNolteHCreticosPMaloneyJWuJBernsteinDIEfficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adultsJ Allergy Clin Immunol20111271728021211643

 PubMed Web of Science ®Google Scholar

MaloneyJBernsteinDINelsonHEfficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trialAnn Allergy Asthma Immunol2014112214615324468255

 PubMed Web of Science ®Google Scholar

BozekAKolodziejczykKWarkocka-SzoltysekBJarzabJGrass pollen sublingual immunotherapy: a double-blind, placebo-controlled study in elderly patients with seasonal allergic rhinitisAm J Rhinol Allergy201428542342725198030

 PubMed Web of Science ®Google Scholar

SwamyRSReshamwalaNHunterTEpigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapyJ Allergy Clin Immunol2012130121522422677046

 PubMed Web of Science ®Google Scholar

WahnUKlimekLPloszczukAHigh-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is effective and safe: A double-blind, placebo-controlled studyJ Allergy Clin Immunol20121304886 e5893 e522939758

 PubMed Web of Science ®Google Scholar

StelmachIKaluzinska-ParzyszekIJerzynskaJStelmachPStelmachWMajakPComparative effect of pre-coseasonal and continuous grass sub-lingual immunotherapy in childrenAllergy201267331232022142341

 PubMed Web of Science ®Google Scholar

PanznerPPetrášMSýkoraTLesnáIKLiškaMBoth sublingual and supralingual routes of administration are effective in long-term allergen-specific immunotherapyAllergy Asthma Proc201132214215021439167

 PubMed Web of Science ®Google Scholar

PanznerPPetrásMSýkoraTLesnáIDouble-blind, placebo-controlled evaluation of grass pollen specific immunotherapy with oral drops administered sublingually or supralinguallyRespir Med200810291296130418585908

 PubMed Web of Science ®Google Scholar

AgostinisFFogliaCBrunoMEFalagianiPEfficacy, safety and tolerability of sublingual monomeric allergoid in tablets given without up-dosing to pediatric patients with allergic rhinitis and/or asthma due to grass pollenEur Ann Allergy Clin Immunol200941617718020128231

 PubMedGoogle Scholar

AhmadiafsharAMaarefvandMTaymourzadeBMazloomzadehSTorabiZEfficacy of sublingual swallow immunotherapy in children with rye grass pollen allergic rhinitis: a double-blind placebo-controlled studyIran J Allergy Asthma Immunol201211217518122761191

 PubMed Web of Science ®Google Scholar

FrewAJPowellRJCorriganCJDurhamSREfficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitisJ Allergy Clin Immunol2006117231932516461133

 PubMed Web of Science ®Google Scholar

WalkerSMPajnoGBLimaMTWilsonDRDurhamSRGrass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trialJ Allergy Clin Immunol20011071879311149996

 PubMed Web of Science ®Google Scholar

DurhamSRWalkerSMVargaEMLong-term clinical efficacy of grass-pollen immunotherapyN Engl J Med1999341746847510441602

 PubMed Web of Science ®Google Scholar

DolzIMartínez-CóceraCBartoloméJMCimarraMA double-blind, placebo-controlled study of immunotherapy with grass-pollen extract Alutard SQ during a 3-year period with initial rush immunotherapyAllergy19965174895008863926

 PubMed Web of Science ®Google Scholar

LeynadierFBanounLDolloisBImmunotherapy with a calcium phosphate-adsorbed five-grass-pollen extract in seasonal rhinoconjunctivitis: a double-blind, placebo-controlled studyClin Exp Allergy200131798899611467988

 PubMed Web of Science ®Google Scholar

PawankarR2013The WAO White Book on Allergy (Update. 2013) Available from: http://www.worldallergy.org/UserFiles/file/WAO-White-Book-on-Allergy_web.pdfAccessed December 2, 2015

 Google Scholar

SedaghatARPhipatanakulWCunninghamMJCharacterization of aeroallergen sensitivities in children with allergic rhinitis and chronic rhinosinusitisAllergy Rhinol (Providence)20145314314525565050

 PubMedGoogle Scholar

Larenas-LinnemannDMichelsADingerHIn the (sub)tropics allergic rhinitis and its impact on asthma classification of allergic rhinitis is more useful than perennial-seasonal classificationAm J Rhinol Allergy201428323223824980234

 PubMed Web of Science ®Google Scholar

CoxLSCasaleTBNayakASClinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgEJ Allergy Clin Immunol201213061327133423122534

 PubMed Web of Science ®Google Scholar

PajnoGBCaminitiLCrisafulliGDirect comparison between continuous and coseasonal regimen for sublingual immunotherapy in children with grass allergy: a randomized controlled studyPediatr Allergy Immunol201122880380721929600

 PubMed Web of Science ®Google Scholar

OttHSieberJBrehlerREfficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT studyAllergy20096491394140119764942

 PubMed Web of Science ®Google Scholar

StelmachIKaczmarek-WoźniakJMajakPOlszowiec-ChlebnaMJerzynskaJEfficacy and safety of high-doses sublingual immunotherapy in ultra-rush scheme in children allergic to grass pollenClin Exp Allergy200939340140819134016

 PubMed Web of Science ®Google Scholar

SeidenbergJPajnoGBBauerCPLa GruttaSSieberJSafety and tolerability of seasonal ultra-rush, high-dose sublingual-swallow immunotherapy in allergic rhinitis to grass and tree pollens: an observational study in 193 children and adolescentsJ Investig Allergol Clin Immunol2009192125131

 PubMed Web of Science ®Google Scholar

Larenas-LinnemannDWhy direct efficacy comparison of SLIT tablets for rhino-conjunctivitis, based on existing data, is non-validAnnals Allergy Asthma Immunol Epub 2016 With permission from Elsevier

 Google Scholar