Short- and long-term real-world effectiveness of omalizumab in severe allergic asthma: systematic review of 42 studies published 2008-2018

Figures & data

Figure 1. Data identification, screening, eligibility and inclusion.

Table 1. Summary of designs, time points of assessments, and effectiveness outcomes reported.

							Time points of assessments reported
Studies on adults	Reference number	Design	Retrospective data pre-omalizumab therapy	Country	Evaluable N at baseline (omalizumab-treated)	Physicians/centers	16 weeks	6 months	1 year	Other
Molimard et al., 2008*	24	Prospective	1 year	France	146					≥ 5 months
Korn et al., 2009*	26	Prospective	1 year	Germany	280	134	✓	✓
Cazzola et al., 2010*	27	Prospective	1 year	Italy	142	13			✓
Bousquet et al, 2011*	30	Prospective	1 year	Various^	272	106	✓			32 weeks
Costello et al., 2011*	31	Retrospective	6 months	Ireland	63	6		✓
Dal Negro et al., 2012	58	Retrospective	1 month	Italy	16					3 years
Rottem et al., 2012*	32	Retrospective	1 year	Israel	33				✓
Rubin et al., 2012*	33	Prospective	Not specified	Brazil	78					Week 12 & Week 20
Schumann et al., 2012*	34	Prospective	16 weeks	Germany	195	85	✓	✓
Sweeney et al., 2012*	35	Retrospective	Not specified	UK	59		Not specified
Tzortzaki et al., 2012*	36	Retrospective	1 year	Greece, Cyprus	60	4	✓		✓	4 years
Vennera et al., 2012*	37	Prospective	1 year	Spain	266	30	✓		✓	2 years
Wittchen et al., 2012	59	Prospective	1 year	Germany	53**					T1: 2 to 3 months T2: 6 to 8 months
Grimaldi-Bensouda et al., 2013*	40	Prospective	1 year	France	374	129				1.67 years (mean)
Kelmenson et al., 2013*	41	Prospective	Not specified	USA	4					5 months
Subramaniam et al., 2013*	42	Retrospective	6 months	Ireland	30			✓
Alfarroba et al., 2014*	43	Retrospective	1 year	Portugal	26			✓	✓	2 years
Caminati et al., 2014	60	Retrospective	Not specified	Italy	59	9				23 ± 16.5 months
Tajiri et al., 2014*	44	Prospective	1 year	Japan	31		✓		✓
Vieira et al., 2014*	45	Prospective	1 year	Portugal	15		✓		✓	2 years
Gouder et al., 2015	61	Prospective	1 year	Malta	22	1	✓		✓	32 weeks
Novelli et al., 2015*	46	Prospective	1 year	Italy	306	26				32 months
Tiro et al., 2015*	47	Prospective	1 year	Mexico	47					3 years
Kupryś-Lipińska et al., 2016	62	Prospective	1 year	Poland	53***	1	✓
Sposato et al., 2016	63	Retrospective	1 year	Italy	105°	18				18–39 y.o.: 30 ± 22 months 40–64 y.o.: 36 ± 22 months ≥ 65 y.o.: 37 ± 22 months
Tat & Cilli 2016	64	Retrospective	Not specified	Turkey	19	1				35.7 ± 17.8 months
de Carvalho-Pinto et al., 2017	65	Prospective	Not specified	Brazil	12	1	✓
Mansur et al., 2017	66	Retrospective	1 year	UK	45					60.7 ± 30.9 months (range 23–121)
Nygaard et al. 2017	67	Retrospective	6 months	Denmark	24	1	✓		✓
Humbert et al., 2018	68	Retrospective	1 year	France	723°°	78			✓	4 to 6 months
Studies with adults and adolescents
Brusselle et al., 2009*	25	Prospective	1 year	Belgium	158	35	✓		✓
Pelaia et al., 2011	69	Prospective	1 month	Italy	16	1				40 weeks (9.2 months)
Barnes et al., 2013*	38	Retrospective	1 year	UK	136	10	✓		✓
Braunstahl et al.*§	39,56,57	Prospective	1 year	Various^^	925		✓		✓	8 ms, 18 ms, 2 years
Özgür et al., 2013	70	Retrospective	1 year	Turkey	26	1			✓	2 years, 3 years, last visit (40.8 ± 8.2 months [range 36–62])
Ancochea, et al., 2014	71	Retrospective	1 year	Spain	214	60				6.3 ± 3.5 months
Niven et al., 2016	72	Prospective	1 year	UK	258	22	✓		✓	8 months
DiBona et al., 2017	73	Retrospective	1 year	Italy	91	2				45.6 ± 31.2 months
Kawamatawong et al., 2017	74	Retrospective	1 year	Thailand	78	10	✓		✓
Maltby et al., 2017	75	Prospective	1 year	Australia	160¶	21¶¶		✓
Paganin et al., 2017	76	Retrospective	1 year	France	164~	10		✓	✓	2 years
Adachi et al., 2018	77	Prospective	1 year	Japan	3593	1001	✓		✓
	Effectiveness assessments reported
Studies on adults	Lung function: FEV1	Lung function: other objective	Lung function: subjective (physician-rated)	GINA	Physician-rated effectiveness: GETE	Quality of life (AQLQ, [mini]AQLQ, EQ5D)	Asthma control: ACT	Asthma control: ACQ	Exacerbations	Day-time symptoms	Night-time symptoms	Work or school days lost	General practitioner visits	Specialist visits	Emergency department visits	Hospitalizations	Hospitalization days	Concomitant corticosteroid use	Other concomitant medications	Adverse events
Molimard et al., 2008*									✓						✓	✓		✓		✓
Korn et al., 2009*			✓			✓			✓	✓	✓	✓			✓	✓				✓
Cazzola et al., 2010*					✓				✓						✓	✓		✓	✓	✓
Bousquet et al, 2011*	✓			✓	✓			✓	✓		✓				✓	✓		✓	✓	✓
Costello et al., 2011*	✓	✓							✓			✓				✓	✓	✓	✓	✓
Dal Negro et al., 2012	✓						✓		✓				✓	✓	✓	✓		✓
Rottem et al., 2012*															✓	✓	✓	✓	✓
Rubin et al., 2012*	✓			✓	✓	✓			✓											✓
Schumann et al., 2012*	✓				✓	✓		✓	✓			✓						✓	✓
Sweeney et al., 2012*																		✓		✓
Tzortzaki et al., 2012*	✓	✓					✓		✓									✓		✓
Vennera et al., 2012*	✓						✓		✓							✓		✓	✓	✓
Wittchen et al., 2012							✓		✓									✓	✓	✓
Grimaldi-Bensouda et al., 2013*															✓	✓		✓
Kelmenson et al., 2013*	✓	✓			✓	✓	✓
Subramaniam et al., 2013*	✓			✓					✓							✓		✓
Alfarroba et al., 2014*	✓			✓			✓		✓	✓	✓							✓	✓	✓
Caminati et al., 2014	✓				✓				✓											✓
Tajiri et al., 2014*	✓	✓		✓		✓		✓	✓						✓	✓
Vieira et al., 2014*	✓						✓		✓				✓	✓	✓	✓		✓	✓	✓
Gouder et al., 2015	✓				✓		✓											✓		✓
Novelli et al., 2015*	✓	✓		✓			✓		✓						✓	✓		✓	✓
Tiro et al., 2015*	✓			✓			✓		✓						✓	✓		✓	✓	✓
Kupryś-Lipińska et al., 2016	✓				✓	✓		✓	✓									✓
Sposato et al., 2016	✓						✓		✓										✓
Tat & Cilli 2016	✓						✓		✓							✓				✓
de Carvalho-Pinto et al., 2017							✓	✓
Mansur et al., 2017	✓							✓							✓	✓		✓
Nygaard et al. 2017	✓						✓		✓
Humbert et al., 2018					✓				✓									✓
Studies with adults and adolescents
Brusselle et al., 2009*	✓			✓	✓	✓			✓	✓	✓		✓	✓	✓	✓		✓	✓	✓
Pelaia et al., 2011	✓								✓									✓	✓	✓
Barnes et al., 2013*	✓	✓							✓						✓	✓	✓	✓
Braunstahl et al.*§	✓				✓	✓	✓	✓	✓	✓	✓	✓	✓		✓	✓		✓		✓
Özgür et al., 2013	✓					✓	✓		✓						✓	✓				✓
Ancochea, et al., 2014	✓				✓	✓				✓	✓							✓	✓
Niven et al., 2016	✓					✓	✓		✓			✓	✓		✓	✓		✓		✓
DiBona et al., 2017																				✓
Kawamatawong et al., 2017							✓		✓						✓	✓		✓
Maltby et al., 2017	✓							✓
Paganin et al., 2017	✓
Adachi et al., 2018					✓				✓			✓			✓	✓		✓		✓

*Study included in prior systematic review Abraham et al., 2016 [48]

§ Sample is from eXpeRience Registry; data are reported in three publications: Braunstahl, Chlumský et al. 2013 [39]; Braunstahl, Chen et al., 2013 [56]; and Braunstahl et al, 2014 [57]

^Belgium, Canada, Denmark, Germany, Hungary, Israel, Italy, Norway, Poland, Spain, Sweden, Switzerland, Turkey, and the United Kingdom

^^ Argentina, Bulgaria, Canada, Cyprus, Czech Republic, Hungary, The Netherlands, Philippines, Portugal, Russia, Slovakia, Slovenia, Spain, Taiwan

** Full sample n = 106, results reported separately for omalizumab-treated group and matched controls receiving usual care without omalizumab; only omalizumab-treated group reported here: effectiveness evaluation n = 53, safety evaluation n = 56

*** Full sample n = 53, effectiveness evalution conducted on n = 16 de novo patients (remainder of sample were continuing omalizumab patients)

° Stratified results reported by age categories 18–39 years (n = 13), 40–64 years (n = 61), ≥65 years (n = 31)

°° Study also includes a cohort of 149 patients age 6–17 years not reported here.

¶ Study also includes a cohort of 17 patients with overlapping COPD not reported here.

¶¶ Description of Australia Xolair Registry design and eligibility from Gibson et al., 2016 [78]

~ Total sample n = 207 of which 43 (20.8%) were non-responders at 6 months and discontinued omalizumab; results reported over 2 years on n = 164 responders.

y.o. = years old.

Table 2. Summary of demographics and baseline characteristics.

	Adult-Only Studies (n = 30)				Adult/Adolescent Studies (n = 12)				All Studies (n = 42)
	Studies	Patients	Mean±SD		Studies	Patients	Mean±SD		Studies	Patients	Mean±SD
Age (years)	29	3499	48.8 ± 12.3		11	5741	54.4 ± 15.8		40	9240	52.3 ± 14.6
Weight (kg)	10	950	73.8 ± 16.6		9	1926	75.3 ± 17.6		19	2876	74.8 ± 17.3
Serum total IgE (IU/mL)	24	3299	393.7 ± 629.2		11	5561	362.7 ± 784.5		35	8860	374.3 ± 737.0
FEV1 (% predicted)	23	1865	66.0 ± 18.9		9	1223	62.6 ± 18.1		32	3088	64.7 ± 18.6
Asthma symptoms
Exacerbations in past year (# events)	17	2379	4.1 ± 4.3		8	1826	3.9 ± 2.2		25	4205	4.0 ± 4.0
ACT at baseline	10	781	16.7 ± 4.7		3	1261	12.5 ± 4.5		13	2042	14.1 ± 4.6
ACQ at baseline	4	324	3.5 ± 1.2		3	1299	2.9 ± 1.0		7	1623	3.0 ± 1.1
AQLQ at baseline	3	162	3.4 ± 1.2		5	1715	3.8 ± 1.3		8	1877	3.8 ± 1.3
Healthcare resource utilization*
Emergency room visits (# per pt/yr)	4	254	2.9 ± 2.3		3	4009	1.9 ± 10.5		7	4263	2.0 ± 10.4
Hospitalizations (# per pt/yr)	12	1527	1.5 ± 1.6		4	4145	0.7 ± 3.0		16	5672	0.9 ± 2.7
	Studies	Patients	n	%	Studies	Patients	n	%	Studies	Patients	n	%
Female gender	29	3499	2129	60.8%	12	5819	3763	64.7%	41	9318	5892	63.2%
Never smoked	18	2607	1807	69.3%	8	5365	3848	71.7%	26	7972	5654	70.9%
Asthma symptoms
Exacerbations in past year (% of pts)	8	1243	1158	93.2%	4	1461	1379	93.9%	14	2704	2536	93.8%
Daytime symptoms (% of pts)	1	280	269	96.1%	3	1297	1158	89.3%	4	1577	1427	90.5%
Nighttime symptoms (% of pts)	2	552	457	82.8%	3	1297	1012	78.0%	5	1849	1469	79.5%
Healthcare resource utilization*
≥ 1 Emergency room visit (% of pts)	3	625	301	48.2%	2	3751	949	25.3%	5	4376	1250	28.6%
≥ 1 Hospitalization (% of pts)	8	1863	673	36.1%	2	3751	801	21.4%	10	5614	1473	26.2%
Prior treatments at baseline
Inhaled corticosteroids (% pts)	19	2900	2856	98.5%	6	800	800	100.0%	25	3700	3656	98.8%
Oral corticosteroids (% pts)	22	2958	1283	43.4%	9	5409	2573	47.6%	31	8367	3856	46.1%
Long-acting β2 agonists (% pts)	18	2884	2778	96.3%	6	800	734	98.0%	24	3684	3562	96.7%
Leukotriene receptor antagonists (% pts)	14	1921	1115	58.0%	6	4229	3388	80.1%	20	6150	4503	73.2%
Theophylline/derivatives (% pts)	11	1396	360	25.8%	5	4203	2482	59.1%	16	5599	2842	50.8%
Anticholinergics (% pts)	5	508	92	18.1%	2	318	92	28.9%	7	826	184	22.3%

Abbreviations: ACT Asthma Control Test; ACQ Asthma Control Questionnaire; AQLQ Juniper Asthma-related Quality of Life; FEV₁ forced expiratory volumn in 1 second; IgE immunoglobulin E; IU international units; kg kilogram; mL milliliters; pt patient; pts patients; yr year

Number of patients reflects number at enrollment.

* In year prior to enrollment.

Table 3. Summary of outcome measures (all studies: n = 42).

	16 weeks				5 to 9 months				12 months
	Studies	Patients	% change from baseline	range of % change	Studies	Patients	% change from baseline	range of % change	Studies	Patients	% change from baseline	range of % change
FEV1 (% predicted)	10	1193	12.5%	6% to 22%	10	1207	10.8%	7% to 44%	11	1814	12.4%	0% to 51%
Asthma symptoms
Exacerbations (% of pts)	2*	211	−81.5%	−53% to −91%	6	995	−55.3%	−29% to −80%	6	5567	−38.4%	−30% to −90%
Exacerbations (# events per pt/yr)	7*	729	−67.3%	−21% to −83%	7	1057	−31.5%	−16% to −82%	13	5712	−62.2%	−45% to −80%
Daytime symptoms (% of pts)	2	438	−66.1%	−61% to −69%	3	520	−68.7%	−53% to −76%	3	1109	−40.5%	−36% to −64%
Nighttime symptoms (% of pts)	2	438	−65.1%	−53% to −72%	4	792	−75.9%	−51% to −84%	3	1109	−59.6%	−49% to −73%
ACT score	8	735	39.1%	14% to 54%	5	363	44.8%	8% to 53%	10	1700	44.5%	23% to 77%
ACQ score	4	291	−41.0%	−31% to −58%	3	569	−34.2%	−17% to −46%	2	956	−32.7%	−32% to −55%
GINA classification	3°	508	63.3%	38% to 81%	2	298	75.4%	61% to 77%	2	184	35.7%	31% to 65%
Quality of Life
AQLQ score	6°	604	43.8%	19% to 128%	5	714	46.1%	33% to 55%	4	1372	28.4%	21% to 55%
EQ5D VAS	1	258	23.0%	23%	1	258	25.0%	25%	2	416	25.1%	24% to 27%
EQ5D Index Utility	1	258	20.0%	20%	1	258	17.0%	17%	2	416	21.7%	19% to 26%
Healthcare resource utilization§
Emergency room visits (# events per pt/yr)	1	78	−90.0%	−90%					5	1320	−80.6%	−33% to −93%
≥ 1 Emergency room visit (% of pts)					2	418	−64.1%	−61 to −70%	1	3593	−55.0%	−55%
Hospitalizations (# events per pt/yr)	2	344	−79.8%	−69% to −83%	2	93	−74.7%	−67% to −91%	8	1753	−76.1%	−34% to −86%
≥ 1 Hospitalization (% of pts)					3	698	−74.5%	−55% to −90%	2	3735	−61.4%	−60 to −96%
Other anti-asthma treatments
ICS (% pts DC or dose reduced)	2*	248	−1.6%	0 to −2%	4	443	−35.7%	−7% to −67%	2	749	−48.1%	−17% to −49%
ICS dose	3	153	−15.9%	−12% to −21%	2	42	−25.5%	−19% to −36%	7	745	−21.5%	−10% to −40%
OCS (% pts DC or dose reduced)	4*	341	−43.4%	−25% to −48%	5	469	−58.8%	−22% to −71%	6	1099	−57.7%	−27% to −76%
OCS dose	2	3646	−51.4%	−51% to −80%	2	79	−55.1%	−45% to −95%	5	4967	−68.6%	−12% to −79%
LABA (% pts DC or dose reduced)	2*	248	−17.8%	−2% to −76%	3°°	293	−47.7%	−13% to −76%
LABA dose									3¶	310	−21.4%	−10% to −34%
LTRA (% pts DC or dose reduced)	3*	326	−23.5%	−18% to −30%	2	267	−36.0%	−20% to −40%	3	378	−28.0%	−9% to −50%
Theophylline (% pts DC or dose reduced)	2	273	−21.1%	−18% to −29%	1	214	−60.0%	−60%	4	404	−31.5%	−5% to −50%
	Studies	Patients	% of patients	% range	Studies	Patients	% of patients	% range	Studies	Patients	% of patients	% range
GETE: good or excellent	8	5290	63.4%	58% to 100%	3	959	67.9%	67% to 100%	5	4181	64.5%	62% to 95%
Safety
Adverse events (% pts)	3*	514	16.2%	5.4% to 25.6%	5	740	23.7%	0% to 36%	4	4039	31.6%	8% to 56%
Serious adverse events (% pts)	2	273	5.1%	3.8% to 5.6%	4	714	13.3%	0% to 24%	4	4151	15.0%	7% to 24%
	23 to 32 months				≥ 36 months
	Studies	Patients	% change from baseline	range of % change	Studies	Patients	% change from baseline	range of % change
FEV1 (% predicted)	7	1508	8.5%	0.1% to 44%	8	305	26.0%	19% to 42%
Asthma symptoms
Exacerbations (% of pts)	4	1303	−63.5%	−55% to −80%	4	165	−60.0%	−29% to −90%
Exacerbations (# events per pt/yr)	4	1232	−83.9%	−71% to −88%	3	95	−70.7%	−54% to −87%
Daytime symptoms (% of pts)	2	951	−41.2%	−40% to −83%
Nighttime symptoms (% of pts)	2	951	−68.6%	−68% to −90%
ACT score	6	1271	45.7%	39% to 90%	7	260	55.6%	24% to 109%
ACQ score	2^	970	−31.6%	−31% to −43%
GINA classification	1	26	69.2%	69%
Quality of Life
AQLQ score					2	951	20.2%	16% to 170%
EQ5D VAS					1	26	24.0%	24%
EQ5D Index Utility					1	26	19.0%	19%
Healthcare resource utilization§
Emergency room visits (# events per pt/yr)	4^	1012	−90.6%	−32% to −94%
≥ 1 Emergency room visit (% of pts)	2^^	353	−86.1%	−80% to −87%
Hospitalizations (# events per pt/yr)	2	1191	−81.8%	−67% to −86%	4	106	−81.1%	−71% to −100%
≥ 1 Hospitalization (% of pts)	2^^	353	−87.2%	−86% to −90%
Other anti-asthma treatments
ICS (% pts DC or dose reduced)	4	395	−57.2%	−8 to −100%
ICS dose	3	307	−29.8%	−5% to −33%	2	107	−31.9%	−13% to −56%
OCS (% pts DC or dose reduced)	4**	1340	−53.1%	−12% to −81%	5	160	−83.1%	−51% to −100%
OCS dose	2	970	−63.6%	−63% to −77%
LABA (% pts DC or dose reduced)	1	26	−8.0%	−8%
LABA dose
LTRA (% pts DC or dose reduced)	1	266	−66.0%	−66%
Theophylline (% pts DC or dose reduced)	1	266	−69.0%	−69%
	Studies	Patients	% of patients	% range	Studies	Patients	% of patients	% range
GETE: good or excellent	2	325	80.8%	77% to 82%
Safety
Adverse events (% pts)	2	325	4.6%	3% to 13%	6	259	9.2%	0% to 12%
Serious adverse events (% pts)	3	999	6.5%	0% to 7%	4	152	0.7%	0% to 1.1%

Abbreviations: ACT Asthma Control Test; ACQ Asthma Control Questionnaire; AQLQ Juniper Asthma-related Quality of Life; DC discontinued; EQ5D European Quality of Life Questionnaire 5 Dimensions; FEV₁ forced expiratory volumn in 1 second; GETE Global Evaluation of Treatment Effectiveness; GINA Global Initiative on Asthma; IgE immunoglobulin E; ICS inhaled corticosteroids; IU international units; kg kilogram; LABA Long-acting β2 agonists; LTRA leukotriene receptor antagonists; mL milliliters; OCS oral corticosteroids; pt patient; pts patients; VAS visual analog scale; yr year

Number of patients reflects number at enrollment.

§ Comparing year preceeding baseline to each follow-up timepoint annualized.

* Follow-up ranged from 8 to 16 weeks.

^ Follow-up was ≥ 23 months.

° Follow-up ranged from 12 to 16 weeks.

^^ Follow-up ranged from 32 to 36 months.

** Follow-up ranged from 20 to 24 months.

°° Follow-up ranged from 6 to 12 months.

¶ Follow-up ranged from 9 to 12 months.

¶¶ Follow-up ranged from 16 to 20 weeks.

Figure 2. Effectiveness outcomes: % increase from baseline for FEV1, ACT, GINA and AQLQ.

Figure 3. Effectiveness outcomes: % decrease from baseline for asthma symptoms and healthcare utilization.

Figure 4. Effectiveness outcomes: % decrease from baseline for concomitant asthma treatments.

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