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

Abstract

Objective: Randomized controlled trials (RCTs) have established the safety and efficacy of omalizumab on clinical parameters, and have also evaluated its impact on patient-reported outcomes (PROs). The purpose of this systematic literature review was to review published data based on PRO endpoints in order to determine the benefit of omalizumab as add-on therapy to inhaled corticosteroids in patients with moderate-to-severe persistent allergic asthma.

Methods: A systematic literature review was conducted of reference databases and recent conferences. RCTs of add-on omalizumab therapy in adults, adolescents, and children with moderate-to-severe persistent asthma were included. Two researchers independently screened and reviewed articles with regards to inclusion and exclusion criteria for relevant studies.

Results: Twenty-six trials met the criteria for inclusion. Of these, PRO measures were included in 19 trials to capture the impact of omalizumab on symptoms, 11 assessed patients for health-related quality-of-life (HRQoL), and four evaluated asthma control. Other PROs related to global evaluation of treatment effectiveness and work productivity. Overall, results demonstrated a significant difference across most PROs in favor of omalizumab add-on therapy vs placebo or comparators.

Conclusions: PROs are an integral part of outcome assessment in clinical trials related to asthma. The RCTs reviewed demonstrate that omalizumab treatment improves PROs in patients with moderate-to-severe persistent allergic asthma, particularly symptom control and HRQoL.

Keywords:

• IgE response underlying allergic asthma and rhinitis
• allergic asthma
• omalizumab
• patient reported outcome measures
• patient reported outcomes

Introduction

Asthma impacts over 330 million people worldwide¹, including ∼24 million individuals in the US and 30 million in Europe^2,3. An allergic component, as evidenced by IgE antibodies to a relevant airborne allergen, manifests in ∼80% of patients with asthma, and is often responsible for severe or treatment-refractory disease^4,5. Omalizumab (Xolair; Novartis Pharmaceuticals Corporation; East Hanover, NJ Genentech USA, Inc.; South San Francisco, CA), an anti-IgE monoclonal antibody, represented the first therapeutic agent that specifically addressed the role of allergy in moderate-to-severe asthma. Omalizumab was first approved by the Therapeutic Good Administration in Australia for the treatment of adults and adolescents with moderate allergic asthma in 2002 and was subsequently approved in the US for adults and adolescents with moderate-to-severe persistent allergic asthma not controlled by inhaled steroids in 2003 and in Europe for severe persistent allergic asthma in 2005. Omalizumab was later approved for use in children aged 6–11 years in Europe (severe persistent allergic asthma) and the US in 2009 and 2016, respectively.

Randomized, double-blind, placebo-controlled studies have established the safety and efficacy of omalizumab on clinical parameters such as asthma exacerbations, systemic corticosteroid use, and lung function^6,7. In addition to the above end-points, it is also important to accurately characterize the effects of omalizumab on the patients’ subjective experience of asthma by PROs. According to the FDA Guidance for Industry, a PRO is defined as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else”⁸. PROs in clinical trials are captured by structured questionnaires called PRO measures (PROMs), also often referred to as “PRO instruments”⁹.

The utility of PROMs in asthma has been well documented. In asthma, generic PROMs such as the Short-Form 36 Health Survey (SF-36) and the Health Utilities Index (HUI) may be used to evaluate general health status¹⁰. Disease-specific PROMs investigate and document the concerns, symptoms, and challenges in patients with asthma. These may be categorized into measures of quality-of-life (e.g., Asthma Quality of Life Questionnaire [AQLQ]), symptoms (e.g., Asthma Symptom Diary), or asthma control (e.g., Asthma Control Test)^11,12. Given the high number of PROMs that have been described in the literature and used in clinical studies in asthma, it is important to evaluate the entire body of patient-reported data to understand the potential impact of a treatment. As such, the rationale for this systematic literature review was to review the PRO data for omalizumab as add-on therapy to inhaled corticosteroids in patients with moderate-to-severe persistent allergic asthma.

Methods

A review of the literature evaluating PROs and their respective PROMs utilized in randomized controlled trials of omalizumab in adults, adolescents, and children with moderate-to-severe persistent asthma was conducted using MEDLINE (via PubMed), EMBASE, and the Cochrane Central Library of Controlled Trials (CENTRAL). The search was run on March 22, 2016, and no limits were placed on the publication date. The search was limited to English-language studies.

The population of interest for the review was patients diagnosed with moderate-to-severe allergic asthma, including children (6–11 years), adolescents (12–17 years), and adults (≥18 years). The intervention of interest was omalizumab (search terms “omalizumab” or “Xolair”). Study designs of interest were randomized controlled trials (RCTs) that had been published in peer-reviewed journals and had results presented. Conference websites were also searched to identify late-breaking RCTs, including the Annual Meeting of the American Academy of Allergy, Asthma, and Immunology (AAAAI); Annual Scientific Meeting of the American College of Allergy, Asthma, & Immunology (ACAAI); Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR); ISPOR Annual European Congress; Annual Academy of Managed Care Pharmacy (AMCP) Nexus; Annual Meeting and Expo of AMCP; and Annual International Conference of the American Thoracic Society (ATS). In addition, published systematic reviews were also evaluated for individual studies of relevance. Non-systematic reviews, editorials, commentaries, letters, case reports or cases series, and theses or dissertations were excluded. A further inclusion criterion was sample size: relevant RCTs were required to have n ≥ 10 patients.

Quality assessment of each included study was undertaken independently by two separate reviewers, with any discrepancies in evaluation resolved by a third reviewer. The quality of included studies was assessed using the Cochrane Collaboration’s tool (Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0) for assessing the risk of bias in RCTs. This tool scores a study based on the following types of bias: selection bias, performance bias, detection bias, attrition bias, reporting bias, or other sources of bias.

The search identified 1,380 studies, of which 1,261 were excluded for the following reasons: small sample size (<10); not a study design of interest; no outcomes of interest; not a population of interest; or was a duplicate study. Based on title and abstract screening, 119 studies potentially met the inclusion criteria for full-text review. After review of the full texts, 93 studies were excluded for the following reasons: not an RCT; presented baseline data only; did not have data on any PROs; not a patient population of interest; was a foreign language publication. The selection process in detail is reported in Figure 1. This systematic literature review identified 26 RCTs for inclusion.

Figure 1. PRISMA study flow.

Results

Summary of studies included

A brief description of the RCTs utilizing PROMs is shown in Table 1. The studies had a broad global representation, with 10 multi-national RCTs included^13–22. The majority of included analyses evaluated patients aged 12 years and older (15 of 26 studies)^{13–18,20,22–27}; five trials included adults, aged 18 years and older, only^21,28–31, and two trials included children aged 6 to <12 years^19,32. The majority of RCTs were large (69% had n > 300 patients). Study duration ranged widely from 16–60 weeks, with a median of 28 weeks (based on the longest follow-up duration reported for a given trial). A total of 85% (n = 22) of studies compared the use of add-on omalizumab to standard of care, including inhaled corticosteroid (ICS) ± long-acting beta agonist (LABA), and other guideline-based treatment. Four studies had no placebo control group and evaluated omalizumab plus standard of care compared to standard therapy alone^13,16,20,26. Analyses in two studies isolated a group of patients designated as “responders” to omalizumab, and included them as a third comparator, along with the placebo arm and either all omalizumab patients or those not responding to omalizumab therapy^18,25.

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.

Overall, the risk of bias in the 26 RCTs reviewed was low across the evaluated domains (e.g., blinding of study personnel and participants, complete outcome assessment, and selective reporting) (Table 2). Many studies did not report the randomization procedure for participants or the procedure for allocation to treatment assignment, both of which are included on the Cochrane Collaboration’s Tool, leading to an unclear assessment of the selection bias. Five of the 26 studies demonstrated a low risk of bias across all domains^{15,19,28,31,33}; two studies had either high risk of bias¹⁶ or the publication did not provide sufficient information to assess the risk of bias²⁶.

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.

PRO concepts evaluated

A wide variety of PRO concepts were assessed in the 26 RCTs reviewed, including symptoms, degree of asthma control, impact on daily life and functioning, and HRQoL. PROMs used to evaluate disease-specific HRQoL included the AQLQ and its derivatives, the mini-AQLQ and the pediatric Asthma Quality-of-Life Questionnaire (PAQLQ), as well as other measures. PROMs for asthma control included the Asthma Control Test (ACT) and Asthma Control Questionnaire (ACQ). Work impairment was also measured in one study using the Work Productivity Activity Impairment–Asthma (WPAI-A)³⁴. A diverse set of scoring systems and diaries were used for symptom assessment, including the Total Asthma Symptom Score (TASS) and the Wasserfallen symptom score. A brief summary of asthma-specific PROMs is provided in Table 3. No trends were evident in the use of specific PROMs across the studies, with the exception of a higher proportion of studies conducted in Europe (or international, multi-center studies) evaluating HRQoL (eight of 15 studies) compared with studies conducted in the US and/or Canada (four of 11 studies).

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.

In addition to reporting on the PROMs of interest, the corresponding minimal important difference (MID) was noted. The MID represents the smallest change in outcome that has been demonstrated to be clinically important. While several publications evaluated whether reported changes in PROMs met the established MID values, for studies without a specified achievement of a MID, the authors compared the change with an established MID value.

Asthma-specific quality-of-life

Asthma-specific quality-of-life in adults was measured using the AQLQ, or its derivative, the mini-AQLQ, in nine studies. As shown in Table 4, adults with allergic asthma treated with omalizumab experienced improvements on the overall AQLQ score from baseline; the difference compared with placebo (and/or standard therapy for persistent severe asthma) was statistically significant in all but two studies^15,30; in these two studies, the change was numerically greater for omalizumab-treated patients, but statistical significance was not reported. The improvement was reported as early as 20 weeks (change of +1.3 vs –0.1 for placebo; p < .001²⁶); similar improvement from baseline were reported in 52-week studies (+1.19²⁴ and +1.30²⁶; both p < .001 vs placebo). Domain analyses in four studies reported significant improvement from baseline at 16 weeks³⁰, at 28 weeks¹⁴, and 52 weeks^17,24 in the AQLQ scores of omalizumab-treated patients compared with placebo-treated patients for the following: symptoms, activity limitation, and environmental exposure. Emotional function was significantly improved with omalizumab compared with placebo in all but the 52-week study by Finn et al.²⁴.

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.

Previous validation has suggested that a change of ≥0.5 points on the AQLQ indicates the MID in HRQoL; a change of ≥1.5 points indicates a large improvement in HRQoL³⁵. Patients treated with omalizumab achieved at least the MID in AQLQ overall score; the mean change from baseline ranged from +0.91 points to +1.32 points at 20–52 weeks^14,24,26,27. Six of the nine studies reported the percentage of patients achieving the MID for the overall AQLQ score; of these, five studies reported that significantly more omalizumab-treated patients had a ≥0.5-point improvement from baseline compared with placebo or control (all p < .05, as shown in Figure 2)^{14,15,24,26,36}. One study reported a marginal difference from placebo (78.8% vs 69.8%; p = .05)²⁷. However, in a sub-group analysis of the proportion of patients who achieved a large improvement in HRQoL, a significantly greater proportion of omalizumab-treated patients achieved a ≥1.5-point improvement compared with placebo (48.1% vs 33.3%; p = .003)²⁷. In a similar assessment at 20 weeks in the study by Rubin et al.²⁶, 41.9% of omalizumab-treated patients achieved a >1.5-point improvement compared with only 2.8% of control patients (p < .001). The mini-AQLQ was used to evaluate the impact of add-on therapy with omalizumab on HRQoL²⁰. At 12 months, patients treated with omalizumab compared to best standard care reported significantly greater improvements from baseline in overall score. A similar trend was observed for all individual domains. A significant difference in the percentage of patients achieving a MID (≥0.5-point improvement) from baseline in overall score was reported for patients treated with omalizumab compared to controls (76.5% vs 41.7%, respectively; p < .001).

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

Asthma-specific quality of life in children (age 6–12 years) was measured using the PAQLQ in two studies (Table 4)^19,37. Significant improvement was reported in one study³⁷. At 28 weeks (study end), patients treated with omalizumab experienced significantly greater changes from baseline as compared to placebo for overall PAQLQ score and the individual activities and symptoms domains (p < .05). For the overall PAQLQ score and across all individual domains, more patients with add-on omalizumab therapy achieved a MID of ≥0.5-point improvement at 20 weeks, with significant differences reported for overall score (46.9% vs 33.7%; p < .05) and the activities domain (50.6% vs 39.5%; p < .05) as compared to the control group³⁷. The change in PAQLQ from baseline to 24 weeks in the clinical trial by Lanier et al.¹⁹ did not achieve statistical significance from placebo (p = .676), but the authors noted that baseline PAQLQ values were high.

Rhinoconjunctivitis-related quality-of-life was also evaluated in two studies of patients with co-morbid allergic asthma and rhinitis in order to assess whether an improvement in asthma response with omalizumab would also improve rhinitis symptoms^25,27. In both studies, a significantly greater proportion of omalizumab-treated patients had a rhinitis response (≥1.0-point improvement on the RQLQ overall score) compared with placebo patients (p < .001 in both studies). The improvement from baseline was also statistically significantly greater for omalizumab vs placebo for all RQLQ domains (activities, sleep, non-nasal/non-ocular symptoms, practical problems, nasal symptoms, eye symptoms, and emotional function; p < .05 for all comparisons)^25,27.

Asthma control

Asthma control was evaluated in four studies: three studies utilized the ACT and/or the C-ACT and one study utilized the ACQ. No significant differences were reported for the omalizumab-treated group vs placebo in the change from baseline at 24–48 weeks in total ACT (5.01 vs 4.36; p = .178)²³ or in the mean total ACT (22.5 vs 22.3; p = .54)³². In adolescents and children treated for 4 months with omalizumab, the difference in the mean change on the ACT (in patients ≥12 years of age) and the C-ACT (patients 4–11 years of age) was 0.94 (favoring omalizumab) and 0.73 (favoring omalizumab) compared with placebo; compared with an ICS boost alone, the difference on the ACT was minimal (0.05). Statistical significance was not reported for these comparisons³³. However, the overall mean change from baseline on the ACT (across all treatment arms) was 2.4 points, which did not exceed the MID for the ACT (≥3.0-point improvement). In a sub-group of children of 4–11 years of age in the study by Busse et al.³², a statistically significant difference in mean total C-ACT score in the previous month between omalizumab and placebo group was recorded at 48 weeks (23.0 vs 22.2, respectively; p = .007). It is important to note that, while the results are statistically significant, the point estimates are close and likely not clinically meaningful. In adolescents (≥12 years of age), the difference in mean ACT score in the previous month between omalizumab and placebo groups was not significant.

When asthma control was measured with the ACQ, omalizumab-treated patients experienced clinically meaningful and statistically significant improvement in control¹⁶. Patients receiving optimized asthma treatment plus omalizumab achieved a MID (≥0.4-point reduction) in overall score from baseline to 16 weeks (–0.78) and at 32 weeks (–0.91); in comparison, patients receiving optimized asthma treatment alone did not (change from baseline of –0.11 and –0.04 at 16 and 32 weeks, respectively). The comparison between the omalizumab and optimized treatment group was statistically significant at both week 16 and 32 (p < .001)¹⁶. While the ACT and the ACQ are commonly used PROMs for asthma control, it is important that results for each be interpreted separately, as a previous study has demonstrated that they are not interchangeable (kappa coefficient for agreement =  0.58)³⁸.

Symptom assessment

A total of 19 studies reported the impact of omalizumab on symptom occurrence. The majority of the studies were either double-blind placebo-controlled (13 of 19) trials or randomized open-label studies (three of 19). In addition, there was one post-hoc analysis of the INNOVATE study¹⁸ and two sub-group analyses of previously conducted studies^20,21. All of the studies that reported symptom-related PROs varied by the time period over which the symptoms were measured (range = 4–52 weeks) and by the type of assessment used to capture asthma symptoms.

The overall assessment of the effect of omalizumab on symptoms is complicated by the variation of scales used and the time in which the symptoms were monitored. Complex assessments, such as the Wasserfallen asthma symptom score, were used in three studies, and the Total Asthma Symptom Scale (TASS) was used in five studies. The Wasserfallen validated scale is a self-administered questionnaire (31 items rated on a 6-point Likert scale) including symptoms of inflammation³⁹, and the TASS is a patient assessment of daytime plus night-time symptoms using a scale of 0 (none) to 4 (severe) plus morning score for symptoms upon waking (yes/no) for a maximum score of 9. The Asthma Symptom Score (range = 0–4, where 4 is severe or breath problems at rest) was also used to record symptoms experienced during the day (four studies) or night (three studies). One study rated individual symptoms such as sneezing and chest symptoms and one study simply counted frequency of night-time awakenings. Lastly, five studies recorded the percentage or number of days with asthma symptoms over a specific recall time period.

A summary of studies that assessed symptoms is provided in Table 5. In comparing the findings across studies, all three studies using the Wasserfallen asthma symptom score reported significantly greater changes from baseline in total score for patients in the omalizumab group compared to the control group^13,20,27, with a significant difference in follow-up scores observed in two studies between treatment groups^20,27. Improvements in mean TASS were significantly greater for omalizumab treatment groups compared to placebo assessed at 28 weeks^14,22,40 and 48 weeks¹⁵, and the total asthma scores at follow-up were significantly lower for patients with omalizumab therapy vs placebo up to 32 weeks³⁶. Daytime and night-time asthma symptom scores were evaluated utilizing a 0 (none) to 4 (severe) scale in four and three studies, respectively. While symptoms generally improved for patients using omalizumab compared to placebo, only one study reported significantly lower daytime and night-time scores for patients treated with omalizumab vs placebo at 26–28 weeks of follow-up (p < .05)²². However, actual night-time awakenings over the 2 weeks prior to the assessment were shown to significantly decrease at 32 weeks (p = .039)¹⁶. A study by Corren et al.²⁹ demonstrated a significant change in the mean area under the curve (AUC) in a chest symptom score (0 = none; 3 = severe) over 16 weeks in favor of omalizumab compared to placebo (p < .001). Similar results were seen in the nasal-ocular symptom score (0 = none; 3 = severe) (p = .0002) and the number of sneezes over a 1-hour allergen challenge (cat allergen) (p = .0169) at 16 weeks.

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.

The number of days with asthma symptoms during the previous 2-week period was shown to be significantly lower with omalizumab compared with placebo in two of three studies that made this assessment^32,41. In Busse et al.³², the number of days with symptoms or limitations was evaluated for each 2-week interval, from the completion of the 12-week wash-in to the study completion. Across the 48 weeks of follow-up, omalizumab-treated patients had significantly fewer mean days (per 2-week interval) of wheezing, interference with activities, and night-time sleep disruptions compared to placebo-treated patients (p ≤ .02)³². In a separate study, the percentages of symptom-free days and symptom-controlled days over each 2-week interval were significantly higher in patients who were considered responders to omalizumab therapy compared with those who were treated with omalizumab and placebo over 26–28 weeks (p < .001)¹⁸. However, when the number of days with asthma symptoms, nights with awakening, and days with impairment in daily activities were counted over a 1-week period on a patient diary card, the change from baseline to 16 weeks between omalizumab and placebo was not significant²⁸.

Other patient-reported outcome measures

Global evaluation of treatment effectiveness (GETE) is a validated PROM that reflects clinical outcomes and HRQoL in patients with asthma, and has been shown to be positively correlated with clinical indices (except lung function), AQLQ, and HRQoL⁴². The GETE can also be physician-reported, but only patient-reported outcomes were summarized here. The GETE was reported in six studies, usually alongside the investigator-rated GETE^{14,16,19,26,27,43}. This PROM evaluated perceived treatment effectiveness after 16 weeks of omalizumab therapy using the following ratings: excellent (complete control of asthma), good (marked improvement), moderate (discernible but limited improvement), poor (no appreciable change), or worsening⁴³. In all six studies, significantly more patients reported their treatment effectiveness as excellent or good with omalizumab compared with placebo or optimized asthma treatment over 16–52 weeks (range = 64.3–81.4% reporting excellent or good with omalizumab vs 28.2–72.0% with placebo or optimized asthma treatment; all comparisons p < .01)^{14,16,19,26,27,43}. The impact of omalizumab on work impairment was measured as an exploratory endpoint in one study, using the Work Productivity and Activity Impairment Questionnaire-Asthma (WPAI-A)²³. At week 24, there were no statistically significant differences between the omalizumab and placebo groups for any of the WPAI-A domains.

Discussion

PROs provide important insights into the patient’s individual experience of a disease process⁴⁴. In asthma, measures of lung function and rescue medication usage may not correlate well with a patient’s actual disease experience, or the impact of treatment on a patient’s HRQoL and functioning^11,12. As such, PRO data provide a chance for patients to provide their input into the impact of treatment, and may influence a patient’s or a physician’s treatment decision-making process. For clinicians who routinely manage patients with asthma, PROs can, thus, be important indicators of a patient’s perception of treatment’s effectiveness. From a payer perspective, PROs can be useful to differentiate treatments with otherwise similar safety and efficacy profiles.

The utility of PROMs in asthma has been well documented and described in the literature^11,12. More than 30 validated PROMs have been utilized in RCTs of asthma. In a previously published systematic review, a total of 87 RCTs published between 1985–2006 were identified that reported on the clinical efficacy and safety of ICS and LABA treatment for adults or children with asthma. Of these 87 studies reviewed, 79 utilized at least one PROM to capture the patients’ experiences during treatment for asthma¹². In our review of omalizumab RCTs in adults, adolescents, and children with moderate-to-severe persistent asthma, PROs were reported by eight PROMs. Across the wide range of studies included, omalizumab-treated patients reported improvement in symptoms, asthma control, and HRQoL that were generally greater than placebo or standard therapy, and were sustained for up to 52 weeks. Six RCTs reported that omalizumab-treated patients achieved clinically and statistically meaningful improvements on the AQLQ overall score; between 57.5–78.8% of omalizumab-treated patients achieved the MID of ≥0.5-point improvement from baseline compared with between 22.2–69.8% of placebo or control patients^{14,15,24,26,27,36}. Omalizumab treatment also demonstrated sustained improvement for up to 48 weeks in asthma symptoms and night-time awakenings, assessed with PROMs such as the asthma symptom score^15,36. The effect of omalizumab on asthma control was less consistent, as the studies did not show a consistent ability of omalizumab-treated patients to achieve the MID on the ACT. However, a study measuring control using the ACQ reported a clinically meaningful and statistically significant improvement in omalizumab-treated patients (p < .001)¹⁶.

It should be noted that most of the PROMs included in this review pre-date the FDA guidance on the use of PROMs to support product labeling⁸. This guidance describes the necessary evidentiary standard required to ensure validity of PROMs, trial design, and statistical analysis plan recommended in order to support product labeling based on PRO-related end-points. As such, while the PROMs identified in this review are widely used to demonstrate treatment benefit in asthma studies, they may not be acceptable for the purpose of product labeling in the US. In general, the selection of a PROM is dependent on what outcome is being measured (e.g., functioning, symptoms, or HRQoL), in what population (e.g., pediatrics or adults), and in context of the use (e.g., by a clinician assessing a patient or a study investigator in the context of a clinical trial).

Limitations of this literature review include that studies published after the cut-off date of the literature search (March 22, 2016) may have been omitted. Of the studies included, while the majority were of good quality (i.e., low risk of bias), the reporting of PROM findings used in the studies was inconsistent. For example, in some studies symptom assessments were reported as “asthma symptom scores” without information regarding the validation of the instrument. Similarly, the reporting of the MID poses an additional limitation, as not all studies reported whether changes from baseline met standard criteria for a clinically meaningful improvement. Finally, publication bias represents another potential source of bias, since studies demonstrating positive findings are reported more often than trials with negative results. In order to avoid inadvertently favoring positive studies associated with the use of omalizumab, the search protocol was designed to impartially select studies meeting the selection criteria, regardless of negative or non-significant findings. The risk of bias within each study was then critically evaluated by two independent reviewers.

Conclusions

Overall, these RCTs have provided evidence that omalizumab treatment improves PROs in moderate-to-severe persistent allergic asthma, particularly symptoms and HRQoL.

Transparency

Declaration of funding

Novartis Pharmaceuticals Corporation funded this research.

Declaration of financial/other relationships

Drs Kavati, Ortiz, and Vegesna are employees of Novartis Pharmaceuticals Corporation, which funded this research. Drs Kavati, Ortiz, and Vegesna are stock shareholders of Novartis Pharmaceuticals Corporation. Dr Corren has received grant or research funding from 3M Pharmaceuticals, Sanofi, Regeneron, Aimmune Therapeutics, and Circassia. Dr Corren has been a consultant or advisor to MedImmune, AstraZeneca, Vectura Group, and Regeneron, and has participated in speakers bureaus for Teva Pharmaceutical Industries, Genentech, Novartis Pharmaceuticals Corporation, and AstraZeneca. Dr Panettieri has received grant or research funding from Theratrophix, OncoArendi Therapeutics, Amgen, RIFM, Vertex Pharmaceuticals, Bristol-Myers Squibb, Gilead, Genentech, Sanofi, and Regeneron. Dr Panettieri has been a consultant or advisor to AstraZeneca and MedImmune, and has participated in speakers bureaus for Boston Scientific and Teva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial relationships to disclose.

Acknowledgments

The authors would like to acknowledge Brett Maiese, PhD, MHS for assistance in the data analysis and Ari Gnanasakthy, MBA, MSc, for revising the early versions of this manuscript. Medical writing and editorial assistance in the development of this manuscript were provided by Xcenda, LLC, Palm Harbor, FL, and this service was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ.