Patient-reported outcomes in moderate-to-severe allergic asthmatics treated with omalizumab: a systematic literature review of randomized controlled trials

Figures & data

Figure 1. PRISMA study flow.

Table 1. Overview of RCTs reviewed.

Study	Patient population (severity)	n	Intervention	Study design (duration)	Study duration	PRO assessed and/or PROM used
						Symptoms/control	HRQoL	Other
Ayres et al.^13 (2004)	Poorly controlled, persistent moderate-to-severe allergic asthma in patients ≥12 years	312	•OMB + BSC •BSC	Randomized, open-label, multi-center, parallel-group	12 months	•Wasserfallen asthma symptom score
Bardelas et al.^23 (2012)	Inadequately controlled, persistent allergic asthma treated w/Step 4 or higher asthma maintenance therapy per 2007 NHLBI guidelines in patients ≥12 years	271	•OMB + current maintenance •PBO + current maintenance	Multi-center, randomized, double-blind, PBO-controlled	24 weeks	•ACT •e-Diary		WPAI-A
Bousquet et al.^16 (2011)	Severe persistent allergic asthma in patients ≥12 years <75 years	404	•OMB + OAT •OAT	International, multi-center, randomized, open-label, parallel-group	32 weeks	•Nocturnal awakenings due to asthma •Patient’s GETE •ACQ •e-Diary
Buhl et al.^17 (2002)	Moderate-to-severe, symptomatic in patients ≥12 years <75 years (extension study of Solèr et al.^22 (2001))	546	•OMB + ICS (BDP) ± LABA •PBO + ICS (BDP) ± LABA	International, multi-center, randomized, double-blind, PBO-controlled, parallel-group (core study + double-blind extension)	52 weeks		AQLQ
Busse et al.^40 (2001)	Severe persistent in patients ≥12 years <75 years	525	•OMB + ICS (BDP) •PBO + ICS (BDP)	Multi-center, randomized, double-blind, PBO-controlled, parallel-group (Phase III)	28 weeks	•TASS
Busse et al.^32 (2011)	Moderate or severe in patients 6–20 years	419	•OMB + guideline-based treatment •PBO + guideline-based treatment	Multi-center, randomized, double-blind, PBO-controlled, parallel-group; The Inner-City Anti-IgE Therapy for Asthma (ICATA) Study	60 weeks	•C-ACT •Number of days in 2 weeks preceding visit; interference w/activity
Chanez et al.^28 (2010)	Uncontrolled severe persistent in patients ≥18 years	31	•OMB + ICS (BDP equivalent) + LABA •PBO + ICS (BDP equivalent) + LABA	Multi-center, randomized, PBO-controlled, double-blind	16 weeks	•Number of days w/impairment in daily activities per week •Nights w/awakenings •Change in number of days w/impairment in daily activities per week from baseline •ANAES definition of acceptable/optimal control
Corren et al.^29 (2011)	Moderate asthma in patients 18–65 years	69	•OMB + stable asthma treatment •PBO + stable asthma treatment	Multi-center, randomized, double-blind, PBO-controlled, parallel-group	16 weeks	•Chest symptom score •NOSS •Sneezes
Finn et al.^24 (2003)	Severe persistent in patients 12–75 years (extension study of Busse et al.^40 (2001))	525	•OMB + ICS (BDP) •PBO + ICS (BDP)	Data from core study (Busse et al.^40 (2001)) + double-blind extension: multi-center, randomized, double-blind, PBO-controlled	52 weeks		AQLQ
Hanania et al.^15 (2011)	Severe in patients 12–75 years	850	•OMB + ICS (FCS) + LABA •PBO + ICS (FCS) + LABA	Multi-center, randomized, parallel-group, double-blind, PBO-controlled; the EXTRA study	48 weeks	•TASS	AQLQ
Hanania (2013)^45	Severe in patients 12–75 years	850	•OMB + ICS (FCS) + LABA •PBO + ICS (FCS) + LABA	Pre-specified and post-hoc analyses of the EXTRA study (Hanania et al.^15 (2011))	48 weeks	•TASS	AQLQ
Holgate et al.^36 (2004)	Severe in patients 12–75 years	246	•OMB + ICS (FCS) •PBO + ICS (FCS)	Multi-center, randomized, double-blind, PBO-controlled	32 weeks	•TASS	AQLQ
Hoshino and Ohtawa^30 (2012)	Severe persistent in patients 20–75 years	30	•OMB + SAT •SAT	Randomized, controlled, open-label	16 weeks		AQLQ
Humbert et al.^14 (2005)	Severe persistent in patients 12–75 years	482	•OMB + ICS (BDP equivalent) + LABA •PBO + ICS (BDP equivalent) + LABA	Randomized, PBO-controlled, double-blind; the INNOVATE study	28 weeks	•Total clinical symptom score •Total asthma symptom score •Patients’ GETE	AQLQ
Humbert et al.^18 (2008)	Severe persistent in patients 12–75 years (post-hoc analysis of Humbert et al.^14 (2005))	419	•OMB + ICS (BDP equivalent) + LABA •PBO + ICS (BDP equivalent) + LABA	Post-hoc analysis of the INNOVATE study (Humbert et al.^14 (2005))	28 weeks	•Symptom-free days •Symptom-controlled days	AQLQ*
Humbert et al.^25 (2009)	Moderate-to-severe in patients 12–75 years (post-hoc analysis of Vignola et al.^27 (2004))	399	•OMB + ICS (BUD ± LABA; Responders •PBO + ICS (BUD) ± LABA	Post-hoc analysis of the SOLAR study (Vignola et al.^27 (2004))	28 weeks	•Total asthma symptoms score^†	•AQLQ •RQLQ
Lanier et al.^19 (2009)	Moderate-to-severe persistent in patients 6 to <12 years	627	•OMB + ICS (FCS propionate equivalent) •PBO + ICS (FCS propionate equivalent)	Multi-center, international, randomized, double-blind, PBO-controlled, parallel-group	52 weeks	•Daytime asthma symptom score •Night-time awakenings requiring rescue medication •Change in nocturnal asthma symptom score •Patients’ GETE	PAQLQ
Lemanske et al.^37 (2002)	Moderate-to-severe in patients 6–12 years (additional analysis of Milgrom et al.^43 (2001))	334	•OMB + ICS (BDP) •PBO + ICS (BDP)	Additional analysis of a multi-center, randomized, double-blind, PBO-controlled, parallel-group (Milgrom et al.^43 (2001))	28 weeks		PAQLQ
Milgrom et al.^43 (2001)	Moderate-to-severe in patients 6–12 years	334	•OMB + ICS (BDP) •PBO + ICS (BDP)	Multi-center, randomized, double-blind, PBO-controlled, parallel-group	28 weeks	•Daytime asthma symptom score •Nocturnal asthma symptom score •Morning asthma symptom score •Patients’ GETE
Niven et al.^20 (2008)	Inadequately controlled, persistent moderate-to-severe allergic asthma in patients ≥12 years (post-hoc analysis of Ayres et al.^13 (2004))	164	•Subgroup: OMB + BSC (ICS >1000 µg/day BDP equivalent + LABA) •Sub-group: BSC (ICS >1000 µg/day BDP equivalent + LABA)	Post-hoc analysis of an open-label, randomized, multi-center, parallel-group study (Ayres et al.^13 (2004))	12 months	•Wasserfallen asthma symptom score	Mini-AQLQ
Noga et al.^21 (2003)	Moderate-to-severe asthma in patients 12–75 (sub-group analysis of Solèr et al.^22 (2001))	35	•OMB + ICS (BDP) ± LABA •PBO + ICS (BDP) ± LABA	Sub-group analysis of an international, multi-center, randomized, double-blind, PBO-controlled, parallel-group study (Solèr et al.^22 (2001), Buhl et al.^17 (2002))	7 months	•Asthma symptom score
Ohta et al.^31 (2009)	Moderate-to-severe persistent asthma in patients 20–75 years	372	•OMB + ongoing asthma therapy [including high-dose ICS (BDP equivalent) ± other controller medications] •PBO + ongoing asthma therapy	Multi-center, randomized, double-blind, PBO-controlled	16 weeks	•Asthma symptom score
Rubin et al.^26 (2012)	Uncontrolled, severe persistent asthma in patients ≥12 years	116	•OMB + LABA + ICS (FCS equivalent) •LABA + ICS (FCS equivalent)	Multi-center, randomized, open-label, parallel group (QUALITX)	20 weeks	•Patients’ GETE	AQLQ
Solèr et al.^22 (2001)	Moderate-to-severe, symptomatic in patients ≥12 years <75 years	546	•OMB + ICS (BDP) ± LABA •PBO + ICS (BDP) ± LABA	International, multi-center, randomized, double-blind, PBO-controlled, parallel-group	7 months	•Daytime score by patient diary: 0–4 (4 being worst) •Night-time score by patient diary: 0–4 (4 being worst) •TASS
Sorkness et al.^41 (2013)	Moderate or severe asthma in patients 6–20 years (post-hoc analysis of Busse et al.^32 (2011))	419	•OMB + guideline-based treatment •PBO + guideline-based treatment	Post-hoc analysis of a multi-center, randomized, double-blind, PBO-controlled, parallel-group study; ICATA Study (Busse et al.^32 (2011))	60 weeks	•Asthma-related symptoms
Teach et al.^33 (2015)	Diagnosis or symptoms for more than 1 year, one or more asthma exacerbations (requiring systemic corticosteroids) or hospitalization within the prior 19 months, a positive skin test response to one or more perennial allergen in patients 6–17 years	513	•OMB (with inhaled PBO) + guidelines-based care •Guidelines-based care (with inhaled and injected PBO)	3-arm, randomized, double-blind, double PBO-controlled, multi-center clinical trial (PROSE)	4–9 month run-in phase, 4 month intervention phase	•ACT •C-ACT •Asthma-related symptoms
Vignola et al.^27 (2004)	Moderate-to-severe in patients 12–75 years	405	•OMB + ICS (BUD) ± LABA •PBO + ICS (BUD) ± LABA	Multi-center, randomized, double-blind, parallel-group, PBO-controlled; the SOLAR study	28 weeks	•Wasserfallen total asthma symptom score •Wasserfallen total rhinitis clinical symptom score •Patient’s GETE	•AQLQ •RQLQ

* Baseline data only for QoL reported.

† Baseline data only for symptom assessment reported.

Abbreviations. ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; AQLQ, Asthma Quality of Life Questionnaire; BDP, beclomethasone dipropionate; BSC, best standard care; BUD, budesonide; C-ACT, Childhood Asthma Control Test; FCS, fluticasone; ICS, inhaled corticosteroid; GETE, global evaluation of treatment effectiveness; HRQoL, health-related quality-of-life; ICATA, Inner-City Anti-IgE Therapy for Asthma; LABA, long-acting beta agonist; NOSS, nasal/ocular symptom scale; OAT, optimized asthma treatment; OMB, omalizumab; PAQLQ, Pediatric Asthma Quality of Life Questionnaire; PBO, placebo; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; SAT, stable asthma treatment; TASS, Total Asthma Symptom Score; WPAI-A, Work Productivity and Activity Impairment Questionnaire-Asthma.

Table 2. Assessment of risk of bias using the Cochrane collaboration tool.*

Study	Data years	Selection bias		Performance bias	Detection bias	Attrition bias	Reporting bias	Other bias
		Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Other sources of bias
Ayres et al.^13 (2004)	NR	C	C	A	A	A	A	A
Bardelas et al.^23 (2012)	NR	C	C	A	A	A	A	A
Bousquet et al.^16 (2011)	NR	A	A	B	B	A	A	A
Buhl et al.^17 (2002)	NR	C	C	A	A	A	A	A
Busse et al.^40 (2001)	NR	C	C	A	A	A	A	A
Busse et al.^32 (2011)	2006–2008	C	C	A	A	A	A	A
Chanez et al.^28 (2010)	2006–2008	A	A	A	A	A	A	A
Corren et al.^29 (2011)	NR	C	C	A	A	A	A	A
Finn et al.^24 (2003)	NR	C	C	A	A	A	A	A
Hanania et al.^15 (2011)	NR	A	A	A	A	A	A	A
Holgate et al.^36 (2004)	NR	C	C	A	A	A	A	A
Hoshino and Ohtawa^30 (2012)	NR	C	C	A	A	A	A	A
Humbert et al.^14 (2005)	NR	C	C	A	A	A	A	A
Humbert et al.^18 (2008)	NR	C	C	A	A	A	A	A
Humbert et al.^25 (2009)	NR	C	C	A	A	A	A	A
Lanier et al.^19 (2009)	NR	A	C	A	A	A	A	A
Lemanske et al.^37 (2002)	NR	C	C	A	A	A	A	A
Milgrom et al.^43 (2001)	NR	C	C	A	A	A	A	A
Niven et al.^20 (2008)	NR	C	C	A	A	A	A	A
Noga et al.^21 (2003)	NR	C	C	A	A	A	A	A
Ohta et al.^31 (2009)	NR	A	A	A	A	A	A	A
Rubin et al.^26 (2012)	NR	C	C	C	C	A	A	A
Solèr et al.^22 (2001)	NR	C	C	A	A	A	A	A
Sorkness et al.^41 (2013)	2006–2008	C	C	A	A	A	A	A
Vignola et al.^27 (2004)	NR	C	C	A	A	A	A	A

* Scoring key: A = Low Risk; B = High Risk; C = Unclear Risk.

Italic text generally indicates good quality, bold text indicates poor quality, and roman text indicates unclear or not determined.

NR, not reported.

Table 3. Characteristics of disease-specific PROMs identified in the 26 studies reviewed.

Measure	Objective and target population	Content validation	Domains	MID	# Items	Administration mode	Recall period
AQLQ	To measure the functional impairments that are most troublesome to adults with asthma Population age range: 17–70 years	Yes	Symptoms Activity limitations Emotional function Environmental stimuli	0.5	32	Self-administered Interviewer administered	2 weeks
Mini-AQLQ	To measure the functional impairments that are most troublesome to adults with asthma Population age range: 17–70 years	Yes	Symptoms Activity limitations Emotional function Environmental stimuli	0.5	15	Self-administered	2 weeks
PAQLQ	To measure the functional impairments that are most troublesome to children with asthma Population age range: 7–17 years	Yes	Symptoms Activity Emotional function	0.5	23	Self-administered Interviewer administered	1 week
ACT	To identify patients with poorly controlled asthma Population age range: ≥12 years	Yes	Asthma control	3.0	5	Self-administered Interviewer administered	4 weeks
C-ACT	To assess asthma control in children Population age range: 4–11 years	Yes	Child Caregiver	3.0	7	Self-administered (child) Interviewer administered	Child: 1 day Caregiver: 4 weeks
ACQ6	To measure the adequacy of clinical asthma control Population age: Adults	Yes	Symptoms Beta-agonist use	0.4	6	Self-administered	1 week
RQLQ	To measure the functional impairments that are most troublesome to adults as a result of rhinoconjunctivitis Population age: Adults	Yes	Overall Activity limitations Sleep impairment Non-nasal or non-ocular symptoms Practical problems Nasal symptoms Eye symptoms Emotional function	0.5	28	Self-administered	1 week
WPAI-A	To measure the loss of productivity due to asthma Population age range: ≥16 years	Yes	Work Daily activities	NR	6	Self-administered	1 week

Abbreviations. ACQ6, Asthma Control Questionnaire; ACT, Asthma Control Test; AQLQ, Asthma Quality-of-Life Questionnaire; C-ACT, Childhood Asthma Control Test; MID, minimal important difference; PAQLQ, Pediatric Asthma Quality-of-Life Questionnaire; RQLQ, Rhinoconjunctivitis Quality-of-Life Questionnaire; WPAI-A, Work Productivity and Activity Impairment Questionnaire–Asthma; NR, Not reported.

Table 4. Studies that used AQLQ (overall score), mini-AQLQ, or PAQLQ.

Study	Intervention	Control	n	Baseline scores	Change in overall AQLQ/mini-AQLQ/Overall PAQLQ*	Time	Achieved MID^§
Buhl et al.^17 (2002)	OMB + ICS ± LABA	PBO + ICS ± LABA	Core: 546 Ext.: 483	PBO: 4.36 OMB: 4.43	OMB scores were higher than PBO (p = NR) The change from baseline was greater for OMB vs PBO (p < .001)^A	52 weeks	Not reported
Finn et al.^24 (2003)	OMB + ICS	PBO + ICS	Core: 525 Ext.: 460	Not reported	LSM change from baseline^B PBO: 0.91 OMB: 1.19 p < .01	52 weeks^C	Yes
Hanania et al.^15 (2011)	OMB + ICS + LABA	PBO + ICS + LABA	850	PBO: 3.9 OMB: 4.0	Difference in change from baseline for OMB vs PBO: 0.29 Significant (p = not reported)	48 weeks	Not reported
Holgate et al.^36 (2004)	OMB + ICS	PBO + ICS	246	Not reported	% of patients with ≥0.5 change from baseline: PBO: 38.6% OMB: 57.5% p < .01	32 weeks	Yes
Hoshino and Ohtawa^30 (2012)	OMB + SAT	SAT	30	Not reported	Median change from baseline: SAT: +0.28 OMB + SAT: +1.47^E p = Not reported	16 weeks	Yes
Humbert et al.^14 (2005)	OMB + ICS + LABA	PBO + ICS + LABA	482	Not reported	LSM change from baseline: PBO: 0.46 OMB: 0.91 Difference: 0.45; p < .001	28 weeks	Yes
Lanier et al.^19 (2009)	OMB + ICS	PBO + ICS	627	Not reported	LSM difference in Overall PAQLQ score: 0.04 in favor of OMB p = .676	52 weeks	No
Lemanske et al.^37 (2002)	OMB + ICS	PBO + ICS	334	PAQLQ: PBO: 5.4 OMB: 5.5	% of patients with ≥0.5 change from baseline: PBO: 33.7% OMB: 46.9% p < .05	28 weeks	Yes
Niven et al.^20 (2008)	OMB + ICS + LABA	PBO + ICS + LABA	164	Not reported	Change from baseline on overall mini-AQLQ PBO: 0.17 OMB: 1.32 p < .001	52 weeks	Yes
Rubin et al.^26 (2012)	OMB + LABA + ICS	LABA + ICS	116	LABA + ICS: 3.1 OMB + ICS+ LABA: 3.1	Mean score at 20 weeks: LABA + ICS: 3.0 OMB + ICS + LABA: 4.4 p < .001 Change from baseline: LABA + ICS: –0.1 OMB + ICS + LABA: 1.3 p < .001	20 weeks^D	Yes^E
Vignola et al.^27 (2004)	OMB + ICS ± LABA	PBO + ICS ± LABA	405	PBO: 4.0 OMB: 4.0	% of patients with ≥1.0-point change from baseline: PBO: 67.3% OMB: 50.0% p = .001	28 weeks	Yes

* Scores on the AQLQ, mini-AQLQ and PAQLQ range from 1–7; a higher score indicates better quality-of-life.

§ Reported here whether the OMB group change from baseline achieved the MID (defined as ≥0.5) or the proportion of patients achieving this MID.

^A15, 28 weeks available; ^BBaseline data available; ^C16, 28 weeks available; significant findings reported at 28 weeks for change from baseline in Emotions domain (p < .05); ^D12 weeks available; ^EMID reported at alternate timepoints.

Abbreviations. AQLQ, Asthma Quality-of-Life Questionnaire; ICS, inhaled corticosteroid; LABA, long-acting beta agonist; MID, minimal important difference; N/A, not available; OMB, omalizumab; PAQLQ, Pediatric Asthma Quality-of-Life Questionnaire; PBO, placebo; SAT, stable asthma treatment.

Figure 2. Percentage of patients achieving MID on overall AQLQ.

Table 5. Studies that used patient-reported symptoms.

Study	Comparison	Symptom measure	Reported change	Timepoint	p-value
Ayres et al.^13 (2004)	OMB + BSC vs BSC only	Wasserfallen total asthma symptom score (reduction from baseline indicates improvement)	Change from baseline, mean: OMB: –6.2 BSC: –0.7	52 weeks	<.001
Bousquet et al.^16 (2011)	OMB + OAT vs OAT only	Night-time awakenings	Change from baseline: OMB: –4.05 OAT: –2.72	32 weeks	.039
Busse et al.^40 (2001)	OMB + ICS (BDP) vs PBO + ICS (BDP)	TASS (reduction from baseline indicates improvement)	OMB significantly improved asthma scores vs placebo after week 4	28 weeks	<.01
Busse et al.^32 (2011)	OMB + guideline-based treatment vs PBO + guideline-based treatment	Number of days with symptoms during the previous 2 weeks, mean ± SE	Asthma-related symptoms OMB: 1.48 ± 0.10 vs PBO: 1.96 ± 0.10; Difference: –0.48 (95% CI: –0.77, –0.20)	48 weeks	<.001
			Wheezing OMB: 1.32 ± 0.09 vs PBO: 1.76 ± 0.09; Difference: –0.44 (95% CI: –0.70, –0.17)	48 weeks	.001
			Interference with activity OMB: 0.70 ± 0.07 vs PBO: 0.59 ± 0.05; Difference: –0.17 (95% CI: –0.31, –0.03)	48 weeks	.003
			Night-time sleep disruption OMB: 0.42 ± 0.05 vs PBO: 0.98 ± 0.07; Difference: –0.28 (95% CI: –0.47, –0.09)	48 weeks	.02
			Sub-group analysis: sensitized and exposed to cockroach allergen OMB: –1.1 (95% CI: 0.4, 1.8); treatment effect: 48.5% Sub-group analysis: not sensitized to or exposed to cockroach allergen OMB: –0.4 (95% CI: 0.1, 0.7); treatment effect: 20.5%	48 weeks	.06
		Reduction in number of days in 2 weeks preceding visit vs PBO	Asthma-related OMB: 1.96 to 1.48; difference: 24.5% (1.04; 95% CI: 0.46, 1.62)	48 weeks	<.001
Chanez et al.^28 (2010)	OMB + ICS (BDP equivalent) + LABA vs PBO + ICS (BDP equivalent) + LABA	Number of days with asthma symptoms per week (diary card), median (range)	Change from baseline, OMB: –1.4 (–7 to 3) PBO: 0.0 (–4 to 2)	16 weeks	.140
		Number of nights with awakening per week, median (range)	Change from baseline, OMB: –0.6 (–6 to 1) PBO: –0.3 (–4 to 2)	16 weeks	.405
		Number of days with impairment in daily activities per week, median (range)	Change from baseline, OMB: –0.4 (–7 to 2) PBO: –0.3 (–7 to 2)	16 weeks	.740
		ANAES definition of acceptable/optimal control (score =0)	OMB: 5 patients (25%) PBO: 1 patient (9.1%)	16 weeks	NR
Corren et al.^29 (2011)	OMB + stable asthma treatment vs PBO + stable asthma treatment	Chest symptom score: chest tightness, wheezing, cough and SOB on a 4-point scale (0, none; 3, severe) (reduction from baseline indicates improvement)	AUC of change in score, mean OMB: 2.1; PBO: 5.6 Difference: –3.5 (95% CI: –4.8, –2.2)	16 weeks	<.0001
		NOSS (nasal-ocular symptoms): nasal congestion, runny nose, itching of nose, itching of eyes, watery eyes on a 4-point scale (0, none; 3, severe) (reduction from baseline indicates improvement)	AUC of change in NOSS, mean OMB: 2.5; PBO: 5.2 Difference: –2.7 (95% CI: –4.0, –1.4)	16 weeks	.0002
		Sneezes	Number of sneezes over 1-h challenge, mean OMB: 3.5; PBO: 9.0 Difference: –5.4 (95% CI: –9.9, –1.0)	16 weeks	.0169
Hanania et al.^15 (2011)	OMB + ICS (FL) + LABA vs PBO + ICS (FL) + LABA	TASS (reduction from baseline indicates improvement)	Decrease in score for OMB vs PBO: Difference: –0.26 (95% CI: –0.42, –0.10)	48 weeks	NR
Holgate et al.^36 (2004)	OMB + ICS (FL) vs PBO + ICS (FL)	TASS (reduction from baseline indicates improvement)	OMB lower than PBO	4, 8, 12, 32 weeks	<.05
			OMB lower than PBO	16, 20, 24, 28 weeks	NS
Humbert et al.^14 (2005)	OMB + ICS (BDP equivalent) + LABA vs PBO + ICS (BDP equivalent) + LABA	TASS (reduction from baseline indicates improvement)	Change from baseline: OMB significantly greater compared to PBO	28 weeks	.039
Humbert et al.^18 (2008)	OMB + ICS (BDP equivalent) + LABA vs OMB + ICS (BDP equivalent) + LABA responder group vs PBO + ICS (BDP equivalent) + LABA	Symptom-free days	OMB-treated: 37.2% OMB-responder: 45.8% PBO: 22.6%	26–28 weeks	<.001
		Symptom-controlled days (total symptom score ≤1)	OMB-treated: 47.9% OMB-responder: 56.1% PBO:35.3%	26–28 weeks	<.001
		Symptom-controlled days: days w/morning PEF rate ≥90% of baseline, daytime asthma score ≤1, and night-time asthma score = 0	OMB-treated: 43.9% OMB-responder: 50.8% PBO: 28.0%	26–28 weeks	<.001
Lanier et al.^19 (2009)	OMB + ICS (FL equivalent) vs PBO + ICS (FL equivalent)	Nocturnal asthma symptom score (0–4), mean (SD) (reduction from baseline indicates improvement)	Change from baseline OMB: –0.63 (0.72) Placebo: –0.50 (0.71)	24 weeks	.114
Milgrom et al.^43 (2001)	OMB + ICS (BDP) vs PBO + ICS (BDP)	Daytime asthma symptom score (0–4), Mean (reduction from baseline indicates improvement)	OMB: 0.36 Placebo: 0.54	22 weeks	NR
Niven et al.^20 (2008)	OMB + BSC (ICS >1000 µg/day BDP equivalent + LABA) vs BSC (ICS >1000 µg/day BDP equivalent + LABA)	Wasserfallen asthma symptom score (reduction from baseline indicates improvement)	Change from baseline: OMB: –6.7 vs BSC: 0.5	12 months	<.01
			OMB had greater improvement compared to BSC	3 months	<.05
				6 months	<.01
				9 months	<.05
Noga et al.^21 (2003)	OMB + ICS (BDP) ± LABA vs PBO + ICS (BDP) ± LABA	Asthma symptom score: scale ranging from 0 = no symptoms, to 4 = breathing problems at rest (reduction from baseline indicates improvement)	Daily score, median (range): OMB: 0.5 (0–2.6) PBO: 0.9 (0–2.9)	16 weeks	NR
Ohta et al.^31 (2009)	OMB + ongoing asthma therapy [high-dose ICS (BDP equivalent) ± other controller medications] vs PBO + ongoing asthma therapy	Asthma symptom score, Daily activity score (reduction from baseline indicates improvement)	Change from baseline: PBO had greater improvement compared to OMB	16 weeks	NS
		Asthma symptom score, Sleep score (reduction from baseline indicates improvement)	Change from baseline: OMB had greater improvement compared to PBO	16 weeks	NS
		Asthma symptom score (reduction from baseline indicates improvement)	Change from baseline: OMB had greater improvement compared to PBO	16 weeks	NS
Solèr et al.^22 (2001)	OMB + ICS (BDP) ± LABA vs PBO + ICS (BDP) ± LABA	TASS (reduction from baseline indicates improvement)	Statistically significant differences in favor of OMB seen during the entire stable-steroid phase	28 weeks	≤.001
		Daytime score by patient diary: 0–4 (4 being worst) (reduction from baseline indicates improvement)	Statistically significant differences in favor of OMB seen from week 4 through week 26	28 weeks	≤.05
		Night-time score by patient diary: 0–4 (4 being worst) (reduction from baseline indicates improvement)	Beneficial effect of OMB was evident for night-time symptoms with statistically significant differences in favor of OMB seen from week 4 through week 26	28 weeks	<.01
Sorkness et al.^41 (2013)	OMB + guideline-based treatment vs PBO + guideline-based treatment	Days with asthma-related symptoms	OMB-treated patients had 0.86 less symptom days (per 2-week period)	4 weeks	.04
Teach et al.^33 (2015)	OMB + guideline-based care vs PBO + guideline-based care	Days with asthma-related symptoms	Number of days in 2 weeks preceding visit, mean (SD): OMB: 1.2 (0.09) PBO: 1.8 (0.16) Difference OMB vs PBO: –0.59 (–0.96, –0.23)	Unclear (“fall outcome period”)	NR
Vignola et al.^27 (2004)	OMB + ICS (budesonide) ± LABA vs PBO + ICS (budesonide) ± LABA	Wasserfallen total asthma symptom score (reduction from baseline indicates improvement)	Change from baseline Difference vs PBO: –1.8	28 weeks	<.05 .023
		Wasserfallen total rhinitis clinical symptom score (reduction from baseline indicates improvement)	Change from baseline Difference vs PBO: –3.53	28 weeks	<.001 <.001
		Wasserfallen total combined symptom score (reduction from baseline indicates improvement)	Change from baseline	28 weeks	<.001

Abbreviations. ANAES, French National Agency for Accreditation and Evaluation in Healthcare; AUC, area under the curve; BDP, beclomethasone dipropionate; BSC, best standard care; GETE, global evaluation of treatment effectiveness; ICS, intravenous corticosteroids; LABA, long-acting beta2 agonist; NR, not reported; NS, not significant; OAT, optimized asthma therapy; OMB, omalizumab; PBO, placebo; SD, standard deviation; SOB, shortness of breath; TASS, Total Asthma Symptom Severity Score.

TASS: Total score (patient diary): daytime + nocturnal scores (each, 0–4) + morning score for symptoms upon wakening (yes or no); max score = 9.

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