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Omalizumab (Xolair): Treatment of Adults and Adolescents (12 Years of Age and above) with Chronic Idiopathic Urticaria [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2015 Aug.
The evidence included in this review was derived from three phase 3, double-blind, multi-centre trials that compared three different doses of OMA (75 mg, 150 mg, and 300 mg, administered every four weeks) with placebo in a total of 978 adult and adolescent patients with H1 antihistamine–refractive CIU. Since 75 mg is not an approved dose in Canada, data for the 75 mg dose groups were excluded from this report. ASTERIA I and GLACIAL had a treatment period of 24 weeks’ duration, whereas ASTERIA II was 12 weeks in duration. All trials had a 16-week treatment-free follow-up period thereafter. The primary objective of ASTERIA I and ASTERIA II was to evaluate whether OMA was superior to placebo for improving WISS after 12 weeks in patients with refractory CIU receiving concomitant standard-dose H1 antihistamine therapy. The primary objective of GLACIAL was to evaluate the safety of OMA compared with placebo in patients with refractory CIU receiving H1 antihistamines (up to four times the approved dose) and either H2 blockers or LTRAs, or both as concomitant therapies. Other efficacy outcomes included UAS7 and WNHS. Quality of life was assessed with DLQI, CU-Q2oL, and EQ-5D. End points were measured at 12 weeks, at 24 weeks, and at the end of the treatment-free follow-up period.
The studies were generally of adequate design and assessed clinically relevant outcomes, but relatively high rates of major protocol violations and protocol issues were reported, including enrolment of patients not meeting inclusion and exclusion criteria. The impact of these limitations on the results of the trials is unclear. Baseline characteristics were mostly balanced between groups and were generally reflective of patients with CIU in Canada according to the consulting clinical expert. However, the inclusion and exclusion criteria of GLACIAL were most aligned with common medical practice in Canada in terms of therapies tried before progressing to OMA. A very low proportion of the included patients were adolescent or elderly, thereby limiting conclusions for these subpopulations.
The GLACIAL trial was identified as the most relevant trial to Canadian clinical practice in terms of study population, as patients were required to be symptomatic despite the use of H1 antihistamines at up to four times the approved dose along with H2 antagonists or LTRAs, or both. Results from GLACIAL suggest that OMA 300 mg is superior to placebo for improving UAS7 and its subcomponents (WISS and WNHS) in this population. When compared with placebo at week 12, OMA 300 mg was associated with statistically significant and clinically relevant improvement in UAS7 of approximately 10 points, in WISS of approximately 4.5 points, and in WNHS of approximately 6 points. These responses were maintained at 24 weeks. In comparison with ASTERIA I and ASTERIA II, the magnitude of treatment effects for efficacy outcomes (UAS7, WISS, and WNHS) were generally smaller in GLACIAL, while effect sizes for quality of life measures (DLQI, CU-Q2oL, and EQ-5D) tended to be higher. These observations may reflect a population in GLACIAL that was more resistant to treatment, but one in which improvements in symptoms were associated with a greater potential for improvements in health-related quality of life compared with the less treatment-resistant populations in ASTERIA I and ASTERIA II. Patient group input received by CDR on this submission reflected anxiety, depression, shame (regarding the appearance of affected skin), insomnia, and absenteeism from work as key concerns associated with CIU. Although not all of these outcomes were measured in the included trials, the observed benefits of OMA on CIU symptoms and quality of life can be expected to address these concerns of relevance to patients.
Most of the subgroup analyses of efficacy outcomes were consistent with the main analysis. Nevertheless, patients who had used less than or equal to two prior CIU medications had a statistically non-significant response in WISS compared with placebo, in all trials. This characteristic may reflect less severe or recalcitrant disease; such patients may have had a higher placebo response compared with patients who used more than two prior CIU medications. However, since patients in the studies were not randomized based on number of medications used, this observation is hypothesis-generating at best.
The product monograph for OMA recommends the use of either the 150 mg or the 300 mg dose for CIU. However, in ASTERIA I and ASTERIA II, the 150 mg dose failed to provide a clinically significant response on UAS7, WISS, and WNHS compared with placebo at week 12, even though the differences were statistically significant. After 24 weeks, the differences observed at week 12 were reduced compared with the week 12 results and were not statistically significant. The potential utility of the 150 mg dose was also evaluated by the proportion of patients achieving the WISS MCID or achieving a UAS7 ≤ 6. A statistically significantly higher proportion of patients in the OMA 150 mg group reached the WISS MCID and reached a UAS7 ≤ 6 compared with patients in the placebo groups at 12 weeks. After 24 weeks, only the proportions of patients who reached a UAS7 ≤ 6 were reported, and the difference between the 150 mg group and the placebo group was not statistically significant. Although there were no formal comparisons of the 150 mg and 300 mg doses in the included trials, the available results suggest that the former dose may have lower efficacy and that an appreciable proportion of patients initiated on 150 mg may eventually need to have the dose increased to 300 mg. Moreover, the 150 mg dose was studied in ASTERIA I and ASTERIA II only, therefore the generalizability of the results to real-world practice in which patients are likely to have failed on high doses of H1 antihistamines and one or more unapproved therapies is uncertain.
Other efficacy outcomes in the included trials were quality of life measures such as DLQI, CU-Q2oL, and EQ-5D. OMA 300 mg appeared to be effective for improving quality of life as measured with DLQI and CU-Q2oL compared with placebo at week 12 and week 24. Change from baseline in DLQI exceeded the MCID at both time points, whereas no MCID is known for CU-Q2oL. Results for EQ-5D did not show any statistically significant improvements with OMA at week 12 or week 24. Indeed, the construct validity and the sensitivity to change of this generic instrument for CIU was considered uncertain, as no studies specifically validating EQ-5D in patients with CIU were identified (see Appendix 5: Validity of Outcome Measures); this view was confirmed by the clinical expert consulted for the review.
Outcomes reported after the 16-week treatment-free follow-up period showed that the majority of efficacy outcomes did not maintain statistically significant improvements compared with placebo. This indicates that the response observed following OMA treatment after 24 weeks attenuates after cessation of treatment for most patients. There were no data on the efficacy of OMA upon re-treatment. The duration of treatment required to have a sustained OMA-elicited response has also not been investigated, nor were how or when treatment should be stopped or reinitiated after discontinuation. According to the consulting clinical expert, if patients are hive-free for six months, treatment may be weaned off, but some patients may have CIU for the rest of their lives. Given the chronic nature of the condition, it is possible that OMA will be used as a long-term treatment for CIU, administered either continuously or intermittently.
The listing criteria requested by the manufacturer specify thresholds for UAS7 and DLQI (i.e., UAS7 ≥ 16 or DLQI ≥ 10); these imply that coverage should be restricted to patients with moderate to severe CIU. The threshold for UAS7 was the same as that used for inclusion in the pivotal trials, but no inclusion criteria for DLQI were mentioned in these studies. Furthermore, the consulting clinical expert indicated that these instruments are not generally used in clinical practice, hence the requested listing criteria may be considered burdensome to implement by clinicians and patients.
According to the patient group input received by CDR on this submission (see Appendix 1: Patient Input S), patients who had used OMA experienced relatively mild adverse effects that would not prevent them from using the drug. The safety results of the included trials appeared aligned with this experience. Patients randomized to both OMA doses experienced more AEs than patients in the placebo groups. The most common AEs were nasopharyngitis (7.7%) and headache (6.6%). Nevertheless, the only AE that appeared to be associated with OMA was headache. According to the clinical expert consulted on the review and patient input received by CDR, this AE is unlikely to significantly affect the tolerability of the treatment or result in treatment discontinuation.
AEs leading to withdrawal from treatment (3.4%), WDAEs (1.1%), and SAEs (2.1%) did not occur more frequently in patients who received OMA than in patients who received placebo. The most frequent cause of WDAEs was urticaria (54.5% of all WDAEs). No deaths occurred during the trials. Based on previous studies on OMA for asthma, expert opinion, and drug safety communications from regulatory agencies, three notable harms — arterial thrombotic events, anaphylaxis and malignancies — were identified in the protocol for this review. In the included trials, these notable harms occurred rarely and none of them appeared to be related to study drug. The US FDA7 noted that arterial thrombotic events were shown to be slightly elevated in patients who used OMA (incidence of 0.135% over five years) compared with placebo (incidence of 0.081% over five years). As with other biologic drugs, anaphylaxis may occur with OMA; approximately 0.2% of patients who use OMA experience this AE.8 Malignancies were found to be numerically higher in patients who had OMA (0.5%) versus placebo (0.2%) in the early studies with this drug;8 however, the consulting clinical expert indicated that the concern regarding malignancy risk has waned since these studies were published. A long-term, prospective, observational cohort study in 5,007 patients using OMA and 2,829 not using OMA found that patients who were treated with OMA were not at higher risk of malignancies than those who were not treated with OMA. However, this study reported a higher incidence of AEs (5% more) in patients who used OMA, especially for the following system organ classes: respiratory, thoracic and mediastinal disorders; infections and infestations; and cardiac disorders.9
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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