Efficacy and safety of treatment with omalizumab for chronic spontaneous urticaria: A systematic review for the EAACI Biologicals Guidelines

2.1 Guidelines development group

The EAACI CSU Voting Panel and Steering Committee included clinicians and researchers with different backgrounds (the complete list of experts is available on the EAACI website), who voluntarily participate in the development of the EAACI biologicals guideline. They are referred to as the Guidelines Development Group (GDG).

2.2 Structured question and outcome prioritization

The GDG framed the clinical question as “Is the treatment with omalizumab efficacious and safe for patients with CSU?” (Table 1). For the purpose of this SR, the population was defined as patients 12 years or older with a diagnosis of CSU inadequately controlled by H1-antihistamine treatment. The CSU-related outcomes were prioritized by the GDG group using a 1-9 scale (7 to 9 critical; 4 to 6 important; 1 to 3 of limited importance) as suggested by the GRADE approach. The critical outcomes were: urticaria activity score (UAS) 7, the itch severity score 7 (ISS7), and safety (drug-related adverse events and serious adverse events). Important outcomes were as follows: quality of life (QoL), measured with Dermatology Life Quality Index (DLQI), the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), resource utilization, and rescue medication use (Table 1).

2.3 Data source and search methodology

Electronic algorithms in combination with controlled vocabulary and search terms were used to identify relevant randomized controlled trials (RCTs) in (a) MEDLINE (via PubMed, January 2020); (b) Cochrane Controlled Trials Register (via The Cochrane Library, January 2020); and (c) Embase (via Ovid, January 2020). Search algorithms were adapted to the requirements of each database, and validated filters were used to retrieve appropriate designs (table S1). Additional studies provided by the GDG and previous SR were also evaluated.

2.4 Eligibility criteria and selection of studies

The SR included only RCTs comparing omalizumab versus placebo added to usual care/standard of care in patients with CSU and reporting one of the outcomes of interest as formulated by the GDG (Figure 1). Only studies published in English were included. Abstracts or conference communications not published as full articles in peer-reviewed journals and RCTs using dose or routes not approved by EMA and/or the FDA were excluded. Two reviewers independently screened the references based on the title and abstract followed by eligibility at full-text level. Discrepancies were solved by consensus or with the help of a third reviewer. All citations retrieved were imported into the bibliographic reference software (EndNote X5; Thomson Reuters) to discard duplicates and record screening decisions.

2.5 Data extraction and risk of bias assessment

Details of the study design, patient population, setting, follow-up, and results were extracted by one reviewer and confirmed by a second reviewer. If needed, additional data from the authors of the included studies were requested. The Cochrane Risk of Bias tool for randomized trials was used to assess the risk of bias (ROB).²⁰ The ROB was judged as low, high, or unclear for each domain: random sequence generation, allocation concealment, blinding of participants and personnel, blinding for outcome assessment, incomplete outcome data, and selective reporting.^21-23

2.6 Data synthesis and analysis

Main results are described narratively and included in summary of findings tables. For dichotomous data, results are pooled as incidence rate ratios (IRR) and risks ratios (RR). For continuous data, results are reported as mean differences (MD), with 95% confidence intervals (CI). For each outcome, the change from baseline to the end of the treatment was assessed versus placebo. A random-effects model was used to pool data (Review Manager v 5.3 Cochrane Collaboration, Oxford, UK). Where multiple arms were compared to a common placebo arm, standard errors were adjusted to avoid unit of analysis error.²⁴ Statistical heterogeneity between studies was assessed with the Cochrane chi-square test and the magnitude of heterogeneity with the I2 statistic.^{24, 25} To account for heterogeneity, subgroup analyses were performed for different doses of omalizumab. The median estimate reported in the control arms of the included RCTs was used as baseline risk to estimate absolute effects for each comparison.

2.7 Certainty of the evidence

The certainty (quality) of the evidence of efficacy and safety was rated for each outcome as high, moderate, low, or very low, following the GRADE approach and the standard GRADE domains (risk of bias, imprecision, inconsistency, indirectness, and publication bias).^{26, 27}

For the evaluation of imprecision for each outcome, the following thresholds for the minimal important difference (MID) were considered: 9.5 to 10.0 points for Weekly Urticaria Activity Score,^28-33 4.5 to 5 points for Weekly Itchy-Severity Score ^30-32 and 2.24 to 3.10 for Dermatology Life Quality Index.³⁴

3.1 Search process

The eligibility process is summarized in the PRISMA flow chart (Figure 1). A total of 7,563 unique citations were retrieved from database searches, and 26 were appraised at full-text level. Eleven publications reporting 10 RCTs were included ^35-45 (Table 2, Figure 1). Fifteen publications were excluded due to regulatory unapproved dose, differences in population or outcomes of interest, or duplicate data (Table S2).

3.2 Characteristics of included studies

The characteristics of studies evaluated are detailed in Table 2. All were randomized control trials, conducted between 2004 and 2017, including patients with CSU receiving omalizumab in addition to standard of care versus placebo. Overall, 1,620 patients aged 12 to 75 years old with CSU/CIU who remained symptomatic despite optimized treatment (H1-antihistamine alone or with addition of an H2-antihistamine and/or leukotriene receptor antagonist) were included. The treatment duration ranged from 4 to 24 weeks, and the extended follow-up without medication ranged from 16 to 40 weeks. Only six studies included patients younger than 18, and among those, the range was between 1.8% to 5.3%.

3.3 Evidence of efficacy

The summary of the results and certainty of evidence per outcome is reported in Table 3 for omalizumab 150 mg every 4 weeks and Table 4 for omalizumab 300 mg every 4 weeks. For efficacy, the metanalysis was performed separately for the 2 doses of omalizumab, grouping the studies in two time periods based on the week the outcomes have been measured (4 to 16 weeks and 24 to 28 weeks).

3.4 Evidence for safety

Drug-related adverse events (AE) were reported in three and four RCTs with omalizumab 150 mg and 300 mg, respectively.^{36, 38, 42, 45} All RCTs assessed this end-point at the end of follow-up (24-40 weeks). Both doses may increase the risk of drug-related AE with low certainty of the evidence: RR 1.40 (95%CI 0.63 to 3.13) for omalizumab 150 mg and RR 1.37 (95%CI 0.67 to 2.82) for omalizumab 300 mg. Drug-related serious AE were assessed for omalizumab 300 mg,³³ showing a decrease with moderate certainty of the evidence compared to placebo (RR 0.77; 95% CI 0.20 to 2.91), although results are inconclusive due to the small RR. One study⁴³ reported a single anaphylactic episode during the open-label phase of the study.

4.1 Main findings

The current systematic review shows that omalizumab 300 mg as add-on treatment significantly reduces the signs and symptoms and burden of CSU, with moderate certainty of evidence. High certainty of evidence for efficacy outcomes was not achieved mainly due to imprecision. For the 150 mg dose, the MID is not reached for any of the observed end-points. For both doses, there is an increased likelihood of achieving complete response and a lower risk of experiencing UAS7 worsening after stopping treatment.

Overall, omalizumab improved QoL, but only omalizumab 300 mg achieved clinical significance (above the MID) with high certainty of evidence. Additionally, omalizumab 300 mg showed a significant improvement in QoL when assessed with CU-QoL and a lower risk of experiencing DLQI worsening after stopping treatment.

Both doses probably reduce rescue medication use and may increases drug-related AE; however, with inconclusive results. Omalizumab 300 mg might decrease serious drug-related AE.

All studies were funded by two pharmaceutical companies and reported positive effect results, which might raise a concern of a potential sponsorship bias.

4.2 Results in the context of previous research

In alignment with the results reported by this SR, all previous systematic reviews assessing omalizumab efficacy and safety in adolescent and adults with CSU/CIU report an improvement in symptoms score assessed and highlight the better efficacy of omalizumab 300 mg over the 150 mg dose.^46-51 In the most recent meta-analysis published by Jia et al, however, there was similar efficacy for 150mg, and 300 mg omalizumab, respectively.⁵² Only three SR reported similar results for the impact on quality of life, rescue medication, and safety.^{46, 49, 52} In contrast with the current results, three SR^{46, 49, 52} report a high certainty of evidence for omalizumab 300 mg safety. A possible explanation for this difference is that the current SR for safety the assessment was limited to drug-related AE.

An important difference with previous SRs is that most of them included nonapproved doses of omalizumab and other treatments for CSU/CIU as part of the SR, while the current SR focused only on the licensed doses of omalizumab, making the results more informative to develop recommendations and applicable to daily clinical practice. Another important difference is the assessment of the certainty of evidence using the GRADE approach. With the exception of Urgert et. al., all previous SRs limited their evaluation to the risk of bias. The current SR considered all relevant aspects related with the certainty of evidence like heterogeneity, indirectness, or imprecision of the results. For instance, the use of MID in the assessment of imprecision enabled the evaluation of the clinical relevance of addition of omalizumab for each outcome.

4.3 Limitations and strengths

The current systematic review has a number of strengths. First, an extended systematic search from three main databases was conducted, for both safety and efficacy. Second, rigorous methods, including the use of the GRADE approach to rate the certainty of the evidence, were followed. The outcomes evaluated were prioritized a priori, and the minimal important difference was included, when available. An optimal presentation of results in a friendly user format improves communication of key messages to patients, clinicians, and other stakeholders.

The current SR also has limitations. Only studies published in English were included. However, the studies included in previous systematic reviews were thoroughly evaluated and additional studies suggested through the GDG were considered, which mitigates the risk of missing studies. No observational studies which could inform on outcomes with low quality of evidence (adverse events, rescue medication use) were included; however, they will be considered in formulating recommendations for clinical practice.

4.4 Implications for practice and research

Only omalizumab 300 mg showed an improvement in chronic spontaneous urticaria related critical outcomes, with moderate certainty. There is however a significant improvement in quality of life, with high certainty of evidence.

Short-term safety data are reassuring. More detailed reporting from RCTs is warranted in combination with long-term safety evaluation including observational studies and registries.

The available data supporting the efficacy and safety in the pediatric population are very scarce, which highlights the need for rigorous trials in this population.