University of Southern Denmark
Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria
who remain symptomatic on H1 antihistamines
a randomized, placebo-controlled study
Saini, Sarbjit S; Bindslev-Jensen, Carsten; Maurer, Marcus; Grob, Jean-Jacques; Bülbül
Baskan, Emel; Bradley, Mary S; Canvin, Janice; Rahmaoui, Abdelkader; Georgiou,
Panayiotis; Alpan, Oral; Spector, Sheldon; Rosén, Karin
Published in:
Journal of Investigative Dermatology
DOI:
10.1038/jid.2014.306
Publication date:
2015
Document version:
Final published version
Document license:
CC BY-NC-ND
Citation for pulished version (APA):
Saini, S. S., Bindslev-Jensen, C., Maurer, M., Grob, J-J., Bülbül Baskan, E., Bradley, M. S., Canvin, J.,
Rahmaoui, A., Georgiou, P., Alpan, O., Spector, S., & Rosén, K. (2015). Efficacy and safety of omalizumab in
patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a
randomized, placebo-controlled study. Journal of Investigative Dermatology, 135(1), 67-75.
https://doi.org/10.1038/jid.2014.306
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See related commentary on pg 13
ORIGINAL ARTICLE
Efficacy and Safety of Omalizumab in Patients with
Chronic Idiopathic/Spontaneous Urticaria Who
Remain Symptomatic on H1 Antihistamines: A
Randomized, Placebo-Controlled Study
Sarbjit S. Saini1, Carsten Bindslev-Jensen2, Marcus Maurer3, Jean-Jacques Grob4, Emel Bülbül Baskan5,
Mary S. Bradley6, Janice Canvin7, Abdelkader Rahmaoui6, Panayiotis Georgiou7, Oral Alpan8,
Sheldon Spector9 and Karin Rosén6
ASTERIA I was a 40-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and
safety of subcutaneous omalizumab as add-on therapy for 24 weeks in patients with chronic idiopathic
urticaria/spontaneous urticaria (CIU/CSU) who remained symptomatic despite H1 antihistamine treatment at
licensed doses. Patients aged 12–75 years with CIU/CSU who remained symptomatic despite treatment with
approved doses of H1 antihistamines were randomized (1:1:1:1) in a double-blind manner to subcutaneous
omalizumab 75 mg, 150 mg, or 300 mg or placebo every 4 weeks for 24 weeks followed by 16 weeks of followup. The primary end point was change from baseline in weekly itch severity score (ISS) at week 12. Among
randomized patients (N ¼ 319: placebo n ¼ 80, omalizumab 75 mg n ¼ 78, 150 mg n ¼ 80, 300 mg n ¼ 81), 262
(82.1%) completed the study. Compared with placebo (n ¼ 80), mean weekly ISS was reduced from baseline to
week 12 by an additional 2.96 points (95% confidence interval (CI): 4.71 to 1.21; P ¼ 0.0010), 2.95 points
(95% CI: 4.72 to 1.18; P ¼ 0.0012), and 5.80 points (95% CI: 7.49 to 4.10; Po0.0001) in the omalizumab
75-mg (n ¼ 77), 150-mg (n ¼ 80), and 300-mg groups (n ¼ 81), respectively. The omalizumab 300-mg group met all
nine secondary end points, including a significant decrease in the duration of time to reach minimally
important difference response (X5-point decrease) in weekly ISS (Po0.0001) and higher percentages of
patients with well-controlled symptoms (urticaria activity score over 7 days (UAS7) p6: 51.9% vs. 11.3%;
Po0.0001) and complete response (UAS7 ¼ 0: 35.8% vs. 8.8%; Po0.0001) versus placebo. During the 24-week
treatment period, 2 (2.9%), 3 (3.4%), 0, and 4 (5.0%) patients in the omalizumab 75-mg, 150-mg, 300-mg, and
placebo groups, respectively, experienced a serious adverse event. Omalizumab 300 mg administered
subcutaneously every 4 weeks reduced weekly ISS and other symptom scores versus placebo in CIU/CSU
patients who remained symptomatic despite treatment with approved doses of H1 antihistamines.
Journal of Investigative Dermatology (2015) 135, 67–75; doi:10.1038/jid.2014.306; published online 21 August 2014
INTRODUCTION
Chronic idiopathic urticaria (CIU), also referred to as chronic
spontaneous urticaria (CSU) (Zuberbier et al., 2009a), is
characterized by itchy wheals (hives), angioedema, or both
that recur for 46 weeks and have no apparent external trigger.
H1 antihistamines are licensed as first-line treatment for CIU/
CSU (Zuberbier et al., 2009b), although many patients continue to experience symptoms despite receiving these drugs
at up to four times higher than the approved dose (Asero,
2007; Staevska et al., 2010). Recommended add-on therapy
for patients unresponsive to up-dosing of H1 antihistamines
includes leukotriene receptor antagonists (LTRAs) and
1
Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland, USA; 2Department of Dermatology and Allergy Centre, Odense University Hospital, Odense C,
Denmark; 3Department of Dermatology and Allergy, Charité—Universitätsmedizin Berlin, Berlin, Germany; 4Dermatology Department, Timone Hospital and AixMarseille University, Marseille, France; 5Dermatology Department, Uludağ University Medical Faculty, Bursa, Turkey; 6Genentech, Inc., South San Francisco,
California, USA; 7Novartis Pharmaceuticals UK, Horsham, UK; 8Section on Immunopathogenesis, O&O Alpan, Fairfax, Virginia, USA and 9California Allergy and
Asthma Medical Group and the University of California Medical Center, Los Angeles, California, USA
Correspondence: Karin Rosén, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, USA. E-mail: rosen.karin@gene.com
Abbreviations: AE, adverse event; CIU, chronic idiopathic urticaria; CSU, chronic spontaneous urticaria; DLQI, Dermatology Life Quality Index; IgE,
immunoglobulin E; ISS, itch severity score; LTRA, leukotriene receptor antagonist; MID, minimally important difference; UAS, urticaria activity score; UAS7,
urticaria activity score over 7 days
Received 6 March 2014; revised 2 June 2014; accepted 4 June 2014; accepted article preview online 21 July 2014; published online 21 August 2014
& 2015 The Society for Investigative Dermatology
www.jidonline.org
67
SS Saini et al.
Efficacy and Safety of Omalizumab in CIU/CSU
cyclosporine A (Zuberbier et al., 2009b; Maurer et al., 2013a).
However, these agents have not received regulatory approval
for this indication. Oral corticosteroids are used to treat CIU/
CSU exacerbations, but they are not recommended for longterm treatment because of potential safety concerns with
chronic use (Zuberbier et al., 2009b).
Cutaneous mast cells, blood basophils, and immunoglobulin E (IgE) have been implicated in the pathophysiology of
chronic urticaria (Vonakis and Saini, 2008). Omalizumab, a
humanized IgE monoclonal antibody licensed for the
treatment of moderate-to-severe (US; patients aged X12
years) and severe (Europe; patients aged X6 years) allergic
asthma, recently received approval from the European
Medicines Agency and the US FDA (Food and Drug
Administration) for the treatment of CIU/CSU (European
Medicines Agency, 2014; Genentech, Inc. and Novartis
Pharmaceuticals Corporation, 2014). Omalizumab may have
a beneficial role in CIU/CSU by reducing mast cell and
basophil activation mediated by IgE and its high-affinity
receptor (FceRI) (Saini and MacGlashan, 2002; Beck et al.,
2004; Ong et al., 2005). Data from proof-of-concept and
phase II studies indicated that omalizumab improved
symptoms and had an acceptable safety profile in patients
with CIU/CSU (Gober et al., 2008; Kaplan et al., 2008; Maurer
et al., 2011; Saini et al., 2011).
The phase III clinical trial program for omalizumab consisted of three randomized, double-blind, placebo-controlled
studies in patients with moderate-to-severe H1 antihistamine–
refractory CIU/CSU: ASTERIA I (ClinicalTrials.gov number:
NCT01287117), ASTERIA II (NCT01292473), and GLACIAL
(NCT01264939). ASTERIA I and ASTERIA II evaluated the
efficacy and safety of omalizumab 75 mg, 150 mg, and 300 mg
versus placebo in patients with CIU/CSU who remained
symptomatic despite treatment with approved doses of H1
antihistamines. These studies were similar in design, except
that the double-blind treatment period was twice as long in
ASTERIA I (24 weeks) than in ASTERIA II (12 weeks;
Supplementary Table S1 online). ASTERIA I was conducted
to evaluate the potential effects of treatment over a longer
duration, in part because the symptoms of CIU/CSU wax and
wane over time. In this study, the introduction of an additional
H1 antihistamine was allowed after week 12 with the aim to
reduce patient dropout over the longer treatment period. The
GLACIAL study was conducted to evaluate the safety and
efficacy of omalizumab 300 mg versus placebo in patients
with CIU/CSU who remained symptomatic despite receiving
up to four times the approved dosage of H1 antihistamines and
either an H2 antihistamine or LTRA, or all three in combination. The primary objective of GLACIAL was to assess the
safety of omalizumab in patients who were receiving different
add-on therapies for CIU/CSU, although efficacy end points
from ASTERIA I and II were also evaluated as secondary end
points. Background CIU therapies in the GLACIAL population
were reflective of the standard-of-care treatments typically
used in clinical practice for patients who were refractory to
approved dosages of H1 antihistamines. Results for the
GLACIAL safety study and the shorter ASTERIA II study have
been reported (Kaplan et al., 2013; Maurer et al., 2013b).
68
Journal of Investigative Dermatology (2015), Volume 135
Here, we report results from the longer ASTERIA I study that
evaluated the efficacy and safety of three doses of omalizumab
over a 24-week treatment period in patients with CIU/CSU
who remained symptomatic despite treatment with approved
dosages of H1 antihistamines.
RESULTS
Figure 1 shows the study profile. A total of 319 patients were
randomized and 318 received at least one dose of the study
drug. Overall, 262 (82.1%) patients completed the 40-week
study and 265 (83.1%) patients completed the 24-week
treatment period (Figure 1). Baseline characteristics were
generally similar across groups (Table 1). Diary compliance
was high (490%) throughout the 40-week study and was
similar among groups (Supplementary Table S2 online).
At week 12, mean weekly itch severity score (ISS) decreased
from baseline (primary end point) by 6.46, 6.66, and 9.40
points in the omalizumab 75-mg, 150-mg, and 300-mg
groups, respectively, versus the placebo group (3.63 points;
Table 2). The difference between each omalizumab group and
placebo was significant in favor of omalizumab (75 mg,
P ¼ 0.0010; 150 mg, P ¼ 0.0012; 300 mg, Po0.0001). Reductions from baseline in weekly ISS were observed as early as
week 1 in all groups (placebo, 2.02 points; omalizumab
75 mg, 3.07 points; omalizumab 150 mg, 3.24 points; omalizumab 300 mg, 5.34 points; Figure 2). Median time to reach
the minimally important difference (MID) in weekly ISS was 3,
2, and 1 weeks in the omalizumab 75-mg, 150-mg, and 300mg groups, respectively, versus 4 weeks in the placebo group
(Table 2). Improvements in urticaria activity score (UAS) over
7 days (UAS7; Supplementary Figure S1 online) and weekly
number of hives score (Supplementary Figure S2 online) over
time were similar to those observed for weekly ISS (Figure 2).
Proportions of patients who achieved well-controlled disease
(UAS7p6) and those with complete response (UAS7 ¼ 0) at
week 12 were more than four times higher in the omalizumab
300-mg group than in the placebo group (Figure 3; both
Po0.0001). Significant improvements compared with placebo
were observed on all nine end points in the omalizumab 300mg group, six of nine end points in the omalizumab 150-mg
group, and two of nine end points in the omalizumab 75-mg
group (Table 2; Supplementary Table S3 online). Sensitivity
analyses of the primary end point using different methods for
handling missing data confirmed those of the primary analysis
(see Supplementary Material online).
Magnitudes of mean changes from baseline to week 24 for
weekly ISS, UAS7, weekly number of hives score, and weekly
size of largest hive score for each omalizumab group
(Supplementary Table S3 online) were similar to those
observed at week 12 (Table 2 and Supplementary Table S2
online). However, in the placebo group, magnitudes of mean
changes in these outcomes were greater from baseline to week
24 than to week 12, resulting in generally smaller treatment
effects at week 24. The omalizumab 300-mg group showed
sustained improvements from baseline in symptom scores at
week 24 (Supplementary Table S3 online). After week 24
(follow-up period), mean weekly ISS in the omalizumab
groups increased to values similar to those in the placebo
SS Saini et al.
Efficacy and Safety of Omalizumab in CIU/CSU
483 screened
for eligibility
171 failed screening1
8 rescreened
80 allocated
to placebo
78 allocated
to
omalizumab
75 mg
1 failed rescreening
80 received
treatment
19 discontinued treatment
7 had adverse event
1 was lost to follow-up
1 patient/guardian decision
10 had disease progression3
61 completed treatment
15 discontinued study
2 had adverse event
1 was lost to follow-up
2 patient/guardian decision
10 had disease progression3
65 completed study
80 analyzed
for efficacy
80 analyzed
for safety
77 received
treatment
11 discontinued treatment
2 had adverse event
3 physician decision
3 patient/guardian decision
3 had disease progression3
67 completed treatment
14 discontinued study
1 had adverse event
1 was lost to follow-up
1 physician decision
6 patient/guardian decision
5 had disease progression3
64 completed study
77 analyzed
for efficacy
70 analyzed
for safety4
80 received
treatment
16 discontinued treatment
4 had adverse event
2 physician decision
5 patient/guardian decision
5 had disease progression3
64 completed treatment
16 discontinued study
1 had adverse event
1 physician decision
8 patient/guardian decision
6 had disease progression3
64 completed study
80 analyzed
for efficacy
87 analyzed
for safety4
81 received
treatment
8 discontinued treatment
2 had adverse event
1 physician decision
3 patient/guardian decision
2 had disease progression3
73 completed treatment
12 discontinued study
1 had adverse event
1 physician decision
5 patient/guardian decision
5 had disease progression3
69 completed study
81 analyzed
for efficacy
81 analyzed
for safety
1 not treated2
319
enrolled
80 allocated
to
omalizumab
150 mg
81 allocated
to
omalizumab
300 mg
14-day
24-week treatment period
16-week follow-up
screening period
Primary end point assessment
Figure 1. Patient disposition and study. Gray arrowheads denote study drug treatment on day 1 and at weeks 4, 8, 12, 16, and 20. Black arrow indicates primary
end point assessment at week 12. 1Reasons for screen failure: 14.0% of patients were unwilling to give written informed consent, adhere to the visit schedules, and
meet study requirements; 10.5% of patients were not diagnosed with chronic idiopathic urticaria/spontaneous urticaria refractory to H1 antihistamines at the time
of randomization; and 27.5% of patients were categorized as ‘‘Other, not defined.’’ 2Patient did not receive study drug as a result of not meeting all study eligibility
criteria and was therefore not included in the modified intention-to-treat population. 3Defined as either the worsening of or no improvement in symptoms. 4Seven
patients randomized to the omalizumab 75-mg group received at least one dose of omalizumab 150 mg during the treatment period and were included in the
omalizumab 150-mg group for the safety and pharmacokinetic analyses.
group, but did not return to baseline mean values for the
duration of follow-up (Figure 2).
During the treatment period, the percentage of patients with
a new onset of antihistamine was numerically lower in the
omalizumab 300-mg group (6.2%, n ¼ 5) than in the placebo
(13.8%, n ¼ 11), omalizumab 75-mg (16.9%, n ¼ 13), or
omalizumab 150-mg (12.5%, n ¼ 10) groups. At week 12, a
reduction in rescue medication use from baseline was
observed in the omalizumab 150- and 300-mg groups versus
placebo (Po0.03; Supplementary Table S3 online).
At baseline, mean Dermatology Life Quality Index (DLQI)
scores ranged from 12.8 to 14.0 across groups (Table 1; higher
score ¼ greater impairment). At week 12, mean (standard
deviation) DLQI score decreased from baseline by 10.29
(7.23) points in the omalizumab 300-mg group versus 6.13
(6.25) points in the placebo group (Supplementary Table S3
online). The difference between these groups was significant
in favor of omalizumab (Po0.0001). Improvement in the
Chronic Urticaria Quality-of-Life Questionnaire overall
score at week 12 was consistent with that observed for the
DLQI (Supplementary Table S3 online). Patients in the
omalizumab 300-mg group experienced a greater mean
proportion of angioedema-free days during weeks 4 to 12
(96.1% (95% confidence interval (CI): 93.5–98.7)) versus the
placebo group (88.2% (95% CI: 83.5–93.0); Po0.0001;
Supplementary Table S3 online). The proportion of patients
with angioedema decreased in all groups over the 24-week
treatment period (Supplementary Table S5 online). Overall,
results of the prespecified subgroup and exploratory analyses
(Supplementary Figure S3 online; Supplementary Table S4
online) were generally consistent with those of the primary
analyses.
www.jidonline.org
69
SS Saini et al.
Efficacy and Safety of Omalizumab in CIU/CSU
Table 1. Patient demographic and baseline characteristics at randomization1
Omalizumab
Characteristic
Placebo (n ¼ 80)
Age (years)
40.4 (15.6)
75 mg (n ¼ 77)
40.7 (15.2)
150 mg (n ¼ 80)
41.1 (14.0)
300 mg (n ¼ 81)
42.4 (13.2)
Age group, n (%)
12–17 years
4 (5.0)
5 (6.5)
7 (8.8)
2 (2.5)
18–40 years
41 (51.3)
33 (42.9)
29 (36.3)
34 (42.0)
41–64 years
30 (37.5)
35 (45.5)
41 (51.3)
42 (51.9)
X65 years
5 (6.3)
4 (5.2)
3 (3.8)
3 (3.7)
52 (65.0)
55 (71.4)
64 (80.0)
60 (74.1)
White
64 (80.0)
62 (80.5)
63 (78.8)
74 (91.4)
Black
10 (12.5)
9 (11.7)
9 (11.3)
5 (6.2)
Female, n (%)
Race, n (%)
Other
Weight (kg)
6 (7.5)
6 (7.8)
8 (10.0)
2 (2.5)
83.0 (20.5)
81.1 (19.2)
83.2 (24.4)
81.6 (19.7)
35 (43.8)
38 (49.4)
40 (50.0)
45 (55.6)
29.3 (6.9)
o80 kg, n (%)
Body mass index (kg m
2
28.7 (6.2)
29.4 (6.5)
29.8 (7.7)
Time since diagnosis of CIU/CSU (years)2
)
7.0 (9.7)
7.0 (9.7)
7.6 (9.2)
6.2 (8.0)
CU index test, n (%)3
25 (31.3)
18 (23.4)
16 (20.3)
21 (25.9)
No. of previous CIU/CSU medications
Median (range) total IgE level (IU ml 1)4
5.0 (2.8)
4.7 (2.8)
4.5 (3.2)
4.5 (2.3)
92.0 (1–1,010)
91.0 (1–2,030)
71.0 (1–5,000)
85.5 (1–2,330)
In-clinic UAS5
5.3 (0.8)
5.3 (0.8)
5.3 (0.7)
5.3 (0.8)
UAS76
31.1 (6.7)
31.7 (6.7)
30.3 (7.3)
31.3 (5.8)
Weekly ISS6
14.4 (3.5)
14.5 (3.6)
14.1 (3.8)
14.2 (3.3)
54 (67.5)
49 (63.6)
54 (67.5)
53 (65.4)
Weekly number of hives score6
X13, n (%)
16.7 (4.4)
17.2 (4.2)
16.2 (4.6)
17.1 (3.8)
Overall DLQI score7
14.0 (6.6)
12.8 (6.1)
13.6 (7.1)
13.0 (6.7)
44 (55.0)
35 (45.5)
38 (47.5)
34 (42.0)
6
Angioedema present, n (%)
Abbreviations: CIU/CSU, chronic idiopathic urticaria/chronic spontaneous urticaria; CU, chronic urticaria; DLQI, Dermatology Life Quality Index;
IgE, immunoglobulin E; ISS, itch severity score; UAS, urticaria activity score; UAS7, urticaria activity score over 7 days.
1
Analyses are based on the modified intention-to-treat population. Data are presented as mean (standard deviation) unless otherwise stated.
2
Placebo, n ¼ 78; omalizumab 75 mg, n ¼ 76; omalizumab 150 mg, n ¼ 78; omalizumab 300 mg, n value as stated.
3
Determined using the CU index test (Viracor-IBT Laboratories, Lee’s Summit, MO); n values reflect those for the modified intention-to-treat population except
for omalizumab 150 mg, n ¼ 79.
4
Placebo, n ¼ 77; omalizumab 75 mg, n ¼ 75; omalizumab 150 mg, n ¼ 74; omalizumab 300 mg, n ¼ 80.
5
Defined as the largest value from the day 14 screening visit, day 7 screening visit, and day 1 visit.
6
Based on data collected in a patient daily diary in the 7 days before the first treatment date.
7
n values reflect those for the modified intention-to-treat population except for placebo, n ¼ 79, and omalizumab 75 mg, n ¼ 75.
Safety
During the 24-week treatment period, the proportions of
patients who experienced one or more treatment-emergent
adverse events (AEs) ranged from 57 to 69% in the omalizumab groups versus 51% in the placebo group (Table 3;
Supplementary Table S6 online). Headaches, arthralgia, and
injection-site reactions were more common in the omalizumab groups than in the placebo group. The majority of
AEs were mild or moderate in intensity (Supplementary
Table S7 online).
The proportion of patients with AEs reported as suspected to
be caused by study drug increased as the dose of omalizumab
70
Journal of Investigative Dermatology (2015), Volume 135
increased (Table 3). The dose-dependent trend was not
clustered by a specific AE type. The largest numerical
differences occurred between the omalizumab 300-mg and
placebo groups for headache (4 vs. 0 patients) and injectionsite reactions (3 vs. 1 patient). The majority of AEs suspected to
be caused by study drug were mild (34/50) or moderate in
intensity (14/50); 10 of the moderate events were in the
omalizumab 300-mg group. Two severe events were reported,
one each in the omalizumab 150-mg and 300-mg groups.
During the treatment period, 2 (2.9%), 3 (3.4%), and 0
patients in the omalizumab 75-mg, 150-mg, and 300-mg
groups, respectively, experienced a serious AE compared with
SS Saini et al.
Efficacy and Safety of Omalizumab in CIU/CSU
Table 2. Primary and selected secondary efficacy end points1
Omalizumab
Placebo (n ¼ 80)
75 mg (n ¼ 77)
150 mg (n ¼ 80)
300 mg (n ¼ 81)
Primary end point
Change from baseline in ISS to week 12
Mean (SD)
3.63 (5.22)
6.46 (6.14)
6.66 (6.28)
9.40 (5.73)
2.3 ( 18.5 to 7.5)
6.0 ( 21.0 to 4.0)
6.0 ( 21.0 to 5.0)
10.0 ( 19.5 to 0)
LSM treatment difference versus placebo
(95% CI)
–
2.96 ( 4.71 to
1.21)
P-value versus placebo2
–
0.0010
0.0012
o0.0001
8.01 (11.47)
13.82 (13.26)
14.44 (12.95)
20.75 (12.17)
4.0 ( 39.0 to
14.5)
13.0 ( 42.0 to 7.0)
14.8 ( 40.0 to 4.5)
22.0 ( 40.0 to 1.0)
LSM treatment difference versus placebo
(95% CI)
–
5.75 ( 9.59 to
1.92)
6.54 ( 10.33 to
2.75)
12.80 ( 16.44 to
9.16)
P-value versus placebo2
–
0.0035
0.0008
o0.0001
Median (95% CI)
4.0 (2.0–6.0)
3.0 (2.0–5.0)
2.0 (2.0–3.0)
1.0 (1.0–2.0)
Minimum, maximum
1.0, 12.0 þ
0 þ , 12.0 þ
1.0, 12.0 þ
0 þ , 12.0 þ
Hazard ratio versus placebo (95% CI)
–
1.39 (0.95–2.03)
1.49 (1.04–2.14)
2.34 (1.63–3.36)
P-value versus placebo
–
0.0879
0.0301
o0.0001
29 (36.3)
43 (55.8)
45 (56.3)
61 (75.3)
0.0226
o0.0001
Median (range)
2.95 ( 4.72 to 1.18) 5.80 ( 7.49 to 4.10)
Selected secondary end points
Change from baseline in UAS7 to week 12
Mean (SD)
Median (range)
Time to MID in weekly ISS (weeks)
3
Patients with MID in weekly ISS at week 12, n (%)
P-value versus placebo
–
4
0.0118
Abbreviations: CI, confidence interval; ISS, itch severity score; LSM, least-squares mean; MID, minimally important difference; SD, standard deviation;
UAS7, urticaria activity score over 7 days.
1
Analyses are based on the modified intention-to-treat population with missing week 12 scores imputed using the baseline weekly score.
2
Derived from an analysis of covariance t-test.
3
In this analysis, the hazard ratio represents the likelihood that a patient in a given omalizumab dose group will achieve MID response in weekly ISS relative to
patients in the placebo group at any point in time up to week 12.
4
Not evaluated for statistical significance in accordance with the type 1 error control plan.
4 (5.0%) patients in the placebo group (Table 3;
Supplementary Table S8 online). None of these was assessed
by the investigator to be related to the study drug. There were
no deaths during the study.
There were no observations of treatment-emergent AEs
considered to be malignancies in the omalizumab groups. At
database lock, an event of cervical dysplasia was reported in
one patient (placebo group); however, after receiving the
pathology report for this patient post-database lock, it was
determined that the patient experienced cervical adenocarcinoma in situ (see Supplementary Material online). Three
patients with suspected anaphylaxis (two during omalizumab
treatment and one 142 days post final dose of study drug) were
referred for blinded external adjudication. The two events
during omalizumab treatment were judged to be not anaphylaxis and anaphylaxis not attributed to study drug, respectively. The event 142 days post treatment was judged to be
dipryone-induced anaphylaxis (see Supplementary Material
online).
DISCUSSION
ASTERIA I is one of the largest clinical studies in patients with
H1 antihistamine–refractory CIU/CSU to date. Strengths of this
study include its size and high rates of diary compliance; the
main results were confirmed by the pre-planned sensitivity
analyses. Efficacy results in ASTERIA I were consistent with
those from ASTERIA II and GLACIAL (Kaplan et al., 2013;
Maurer et al., 2013b). The baseline characteristics of patients
were generally similar among the three studies except for the
number of previous medications used for CIU/CSU, which
was slightly higher in GLACIAL (median, 6) than in ASTERIA I
and ASTERIA II (median, 4 for both). In ASTERIA II, significant
improvements from baseline in weekly ISS at week 12
compared with placebo were observed in the omalizumab
150-mg and 300-mg groups, but not in the 75-mg group,
which differs from the results of the current study. It is possible
that this difference may have resulted from the higher placebo
effect in ASTERIA II compared with ASTERIA I (placebo mean
change from baseline: –5.1 and –3.6, respectively). In both
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SS Saini et al.
Efficacy and Safety of Omalizumab in CIU/CSU
0
Placebo
Omalizumab 75 mg
Omalizumab 150 mg
Omalizumab 300 mg
Mean change from baseline
–2
–4
–6
–8
–10
–12
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Study week
Figure 2. Mean weekly itch severity score by study week. Error bars represent standard error of the mean. Arrows indicate study drug injection day. Analyzed on
the basis of the modified intention-to-treat population with missing weekly scores imputed using baseline weekly itch severity scores.
Placebo
(n = 80)
Patients (%)
50
30
Omalizumab
150 mg (n = 80)
Omalizumab
300 mg (n = 81)
P < 0.0001
51.9%
P < 0.0001
40.0%
60
40
Omalizumab
75 mg (n = 77)
P = 0.01481
26.0%
20
11.3%
10
P < 0.0001
35.8%
P = 0.2087
P = 0.45801 15.0%
11.7%
8.8%
1
0
Patients with UAS7-6
Patients with UAS7 = 0
Figure 3. Responder analysis. P-value versus placebo derived from the
Cochran–Mantel–Haenszel w2-test stratified by baseline UAS7 (omedian,
Xmedian) and baseline weight (o80 kg, X80 kg). 1Not evaluated for statistical
significance in accordance with the type I error control plan. UAS7, urticaria
activity score over 7 days.
studies, dose-dependent effects were observed for most of the
prespecified secondary end points, with omalizumab 300 mg
affording greatest efficacy (Maurer et al., 2013b). A return of
symptoms was observed in both the current study and
ASTERIA II (Maurer et al., 2013b) during follow-up, reaching
mean values similar to those in the placebo group but not
returning to baseline values. One possible explanation for this
observation that occurred in all treatment groups is that some
patients may have experienced spontaneous remission of their
disease. The safety data in ASTERIA I confirm those observed
in ASTERIA II (Maurer et al., 2013b) and were consistent with
the established profile of omalizumab in allergic asthma
(Maurer et al., 2011; Saini et al., 2011; Maurer et al.,
2013b; European Medicines Agency, 2014; Genentech, Inc.
and
Novartis
Pharmaceuticals
Corporation,
2014).
72
Journal of Investigative Dermatology (2015), Volume 135
Improvements across all end points for the omalizumab 300mg group were maintained to week 24 in both ASTERIA I and
GLACIAL, and similar safety data were observed in these
studies (Kaplan et al., 2013).
The results of this study may not be generalizable to all
patients with CIU/CSU encountered in clinical practice or to
patients with inducible urticaria. One limitation is that safety
and efficacy have not been studied in patients with treatment
longer than 24 weeks; however, the long-term safety profile of
omalizumab has been well established in allergic asthma (Tan
and Corren, 2011).
In this study, omalizumab significantly reduced symptoms
after 12 weeks of treatment in patients with CIU/CSU who
remained symptomatic despite treatment with approved doses
of H1 antihistamines. Median time to MID in weekly ISS was
shortest in the omalizumab 300-mg group and suggests a
relationship between omalizumab dose and time to onset. Our
current findings not only confirm those from ASTERIA II, but
also extend them beyond 12 weeks of treatment and show a
sustained treatment effect of omalizumab 300 mg for up to 24
weeks on CIU/CSU symptom scores in patients with H1
antihistamine–refractory CIU/CSU. The safety profile for omalizumab over 24 weeks of treatment in patients with CIU/CSU
receiving approved doses of H1 antihistamines was consistent
with the established safety profile in allergic asthma and with
previous observations in CIU/CSU.
MATERIALS AND METHODS
Study design and participants
This was a global phase III, multicenter, randomized, double-blind,
placebo-controlled, parallel-group study to investigate the efficacy
and safety of omalizumab in adult and adolescent patients with
SS Saini et al.
Efficacy and Safety of Omalizumab in CIU/CSU
Table 3. Summary of AEs according to study group over the 40-week study period1
Omalizumab
Patients, n (%)
Any AE
Placebo (n ¼ 80)
75 mg (n ¼ 70)
150 mg (n ¼ 87)
300 mg (n ¼ 81)
53 (66.3)
55 (78.6)
72 (82.8)
57 (70.4)
Any AE during treatment period
41 (51.3)
41 (58.6)
60 (69.0)
46 (56.8)
Any AE during follow-up period
38 (46.9)
32 (40.0)
36 (51.4)
45 (51.7)
Any AE leading to discontinuation of study drug
7 (8.8)
2 (2.9)
4 (4.6)
2 (2.5)
Early discontinuation from study owing to AE
2 (2.5)
2 (2.3)
1 (1.2)
2 (2.5)
Any serious AE
0
5 (6.3)
2 (2.9)
5 (5.7)
Serious AE during treatment period
4 (5.0)
2 (2.9)
3 (3.4)
Serious AE during follow-up period
1 (1.3)
Death
Any AE suspected to be caused by study drug
Any severe AE
0
0
0
4 (5.0)
6 (8.6)
2 (2.3)
0
2 (2.5)
0
0
9 (10.3)
14 (17.3)
13 (16.0)
8 (10.0)
7 (10.0)
8 (9.2)
Severe AE during treatment period
8 (10)
5 (7.1)
5 (5.7)
3 (3.7)
Severe AE during follow-up period
1 (1.3)
3 (4.3)
4 (4.6)
10 (12.3)
Abbreviation: AE, adverse event.
1
Data are for the safety population.
CIU/CSU who remained symptomatic despite treatment with
approved doses of H1 antihistamines. It was carried out at 53 centers
in Denmark, France, Germany, Italy, Poland, Spain, Turkey, and the
US between February 2011 and October 2012. The study comprised
a 14-day screening period, 24-week double-blind treatment period,
and 16-week follow-up period during which omalizumab was not
administered (Figure 1). For the first 12 weeks of the treatment period,
participants were required to maintain stable doses of their prerandomization H1 antihistamine treatment. During weeks 13 to 24 of the
treatment period, patients were allowed to add one additional H1
antihistamine. Patients were permitted to take diphenhydramine
25 mg as needed for itch relief (up to a maximum of three doses
per 24 hours, or less if required by local regulations) throughout the
entire study period.
Patients aged 12–75 years (18–75 years in Germany) with a
diagnosis of CIU/CSU for X6 months who had hives and itching
for X8 consecutive weeks at any time before enrollment despite H1
antihistamine treatment were eligible for study inclusion. Participants
were required to meet the following criteria during the screening
period: the use of an approved dosage of an H1 antihistamine for CIU/
CSU for X3 consecutive days immediately before day 14 with
documented use on the day of the initial screening visit; in-clinic
physician-assessed UAS X4 (range 0–6; see Procedures) on one or
more screening days (day 14, 7, or 1); UAS7 (range 0–42) of
X16 and itch component of UAS7 (range 0–21) of X8 during the 7
days before randomization; willing and able to complete a symptom
diary with an electronic hand-held device (eDiary; Urticaria Patient
Daily Diary) twice daily during the study; and no missing eDiary
entries during the 7 days before randomization. Exclusion criteria
included the following: clearly defined underlying etiology for
chronic urticaria (e.g., cold, pressure); the presence of a disease with
symptoms of urticaria or angioedema, including hereditary or
acquired angioedema; routine doses (daily or every other day for
X5 consecutive days) of systemic steroids, hydroxychloroquine,
methotrexate, cyclosporine, cyclophosphamide, or intravenous
immunoglobulinp30 days of day 14; use of H2 antihistamines or
LTRAsp7 days of day 14; use of H1 antihistamines at greater than
approved dosesp3 days of day 14; history of malignancy; weight
o20 kg; hypersensitivity to omalizumab; or previous treatment with
omalizumab within the previous year.
The study protocol was approved by the institutional review board
or ethics committee at each center. The study was conducted in
accordance with US FDA regulations, the International Conference
on Harmonization E6 Guideline for Good Clinical Practice, Declaration of Helsinki, and any other applicable country laws. The study is
registered with ClinicalTrials.gov, NCT01287117. There was one
amendment to the protocol based on feedback from the US FDA,
Genentech, Inc. staff, and external advisors. The protocol was
amended before the study began and registration at ClinicalTrials.gov
(see Supplementary Material online). An independent data monitoring
committee was established to monitor study conduct and to review
blinded and unblinded safety data at 6-month intervals. A blinded
external anaphylaxis review committee adjudicated suspected cases
of anaphylaxis. Written informed consent was obtained from each
participant or, if the participant was aged o18 years, their parent or
legal guardian.
Randomization and masking
On day 1, patients were randomized in a 1:1:1:1 ratio using an
interactive voice and web response system to receive subcutaneous
doses of omalizumab 75 mg, 150 mg, or 300 mg or placebo at
intervals of 4 weeks during the 24-week treatment period (six doses).
Randomization to treatment group was stratified by baseline weekly
ISS (o13, X13), baseline weight (o80 kg, X80 kg), and study site
(see Supplementary Material online). All patients, evaluating physician(s), the sponsor and its agents, and study personnel were masked
to treatment assignment, except for the site pharmacist(s) who
prepared the study drug but who did not interact with the patients.
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73
SS Saini et al.
Efficacy and Safety of Omalizumab in CIU/CSU
Procedures
Patient-reported outcomes were recorded in the Urticaria
Patient Daily Diary using an electronic hand-held device. Itch
severity, number of hives, and size of largest hive (all scored 0–3)
were recorded every morning and evening. Sleep interference
(range 0 3), activity interference (range 0–3), rescue medication
use (range 0–9), angioedema (yes, no), angioedema treatment,
and healthcare contacts were recorded once daily (see
Supplementary Material online). Urticaria Patient Daily Diary compliance was evaluated throughout the study. The UAS is a
composite eDiary-recorded score with severity intensity ratings
(range: 0 ¼ none to 3 ¼ intense/severe) for the number of hives and
intensity of itch, measured twice daily (morning and evening). The
daily UAS is the average of the morning and evening scores (range 0–
6 points per day), and the UAS7 is the sum of the daily UAS scores
over 7 days (total score 0–42) (Mathias et al., 2010). Health-related
quality of life was assessed using the DLQI questionnaire (range
0–30; higher score represents greater impairment) (Finlay and Khan,
1994).
The primary end point was change from baseline in weekly ISS
(i.e., sum of the daily ISS for 7 days; range 0–21) at week 12.
Secondary end points, all evaluated at week 12, included changes
from baseline in UAS7 and weekly number of hives score; time to
MID response (X5-point decrease) in weekly ISS; the proportion of
patients with UAS7p6; the proportion of weekly ISS MID responders;
changes from baseline in weekly size of largest hive score and overall
DLQI score; the proportion of angioedema-free days during weeks 4
to 12; and the proportion of patients with complete response
(UAS7 ¼ 0). Subgroup analyses were performed based on demographic and baseline variables to evaluate the consistency of the
primary efficacy results. Exploratory end points included the assessment of efficacy end points at week 24, the proportion of itch-free
days and/or hive-free days at weeks 12 and 24, and change from
baseline to week 12 in Chronic Urticaria Quality-of-Life Questionnaire score (see Supplementary Material online). In addition, time to
relapse (loss of UAS7p6) during the follow-up period was assessed in
patients with UAS7 responsep6 at week 24. The proportion of
patients with UAS7p6 at week 24 who maintained their response at
week 40 also was evaluated. Safety was evaluated by recording and
monitoring incidence and severity of AEs and serious AEs and
changes in vital signs and clinical laboratory values. The presence
of antibodies against omalizumab was evaluated from blood samples
at week 40.
Statistical analysis
For the primary end point, analysis of covariance models stratified by
baseline weekly ISS (o13, X13) and baseline weight (o80 kg,
X80 kg) were used to generate least-squares means of the differences
between each of the omalizumab groups and the placebo group.
Similar models were used for the secondary end points that measured
change from baseline. Efficacy analyses were conducted using data
from the modified intention-to-treat population (i.e., randomized
patients who received one or more doses of study drug). Missing
data at week 12 were imputed with the baseline observation carried
forward in analyses of end points evaluating change from baseline to
week 12 (except for the DLQI, for which no imputation was
performed). All statistical tests were two-sided with an overall
significance level of 0.05. Adjustments for multiple comparisons
74
Journal of Investigative Dermatology (2015), Volume 135
were performed according to the type I error control plan (see
Supplementary Material online).
The sample size for this study was based on safety and regulatory
considerations. The estimation of power for efficacy assumed a mean
change from baseline to week 12 in weekly ISS of 9 points in the
omalizumab groups and 3.5 points in the placebo group, with a
common standard deviation of 6 points and an early discontinuation
rate of 15% by week 12; enrollment of 300 patients (75 in each
group) would yield B98% power to detect a treatment effect for the
primary end point.
CONFLICT OF INTEREST
SSS has received research support from Astra-Zeneca, Genentech, Inc., the
National Institutes of Health, and Novartis, and has served as a consultant to
Array, Genentech, Inc., Kendle, Medimmune, Novartis, and Pharmacyclics.
SSS also serves as an interest section leader for American Academy of Allergy,
Asthma & Immunology, section editor for UpToDate, and section editor for the
Journal of Investigative Dermatology. CB-J has received research funding from
Genentech, Inc., Meda, MSD, Novartis, Schering-Plough, Shire, Stallergenes,
and Termo Fisher and has served as a speaker for Faes Farma, MSD, and Termo
Fisher. MM has received research funding from Almirall, Faes Farma, Novartis,
MSD, UCB, and Uriach and has served as a speaker and/or advisor for
Almirall, Genentech, Inc., Merckle Recordati, Moxie, MSD, Novartis, SanofiAventis, Schering-Plough, UCB, and Uriach. J-JG has received funding and/or
honoraria for advisor or speaker functions from Almirall, Bristol-Myers Squibb,
Celgene, GlaxoSmithKline, Meda, Merck, and Roche. SS has received research
funding from Array, Astra-Zeneca, Forest, Genentech, Inc., GlaxoSmithKline,
Johnson & Johnson, KaloBios, Merck, Mylan, Novartis, Revalesio, Rigel,
Roxane, Sanofi-Aventis, Teva, and Vectura. KR is employed by Genentech,
Inc. and receives stock/stock options from Roche. AR is employed by
Genentech, Inc. and receives stock/stock options from Roche. MSB is
employed by Genentech, Inc. and receives stock options from Roche. JC is
employed by and receives stock/stock options from Novartis Pharma. PG is
employed by and receives stock/stock options from Novartis Pharma AG. The
remaining authors declare no conflict of interest.
ACKNOWLEDGMENTS
The ASTERIA I study was funded by Genentech, Inc., South San Francisco, CA,
and Novartis Pharma AG, Basel, Switzerland. Medical writing support for this
manuscript was provided by Alison Gagnon of Excel Scientific Solutions and
funded by Genentech, Inc., and Novartis Pharma AG. The trial was registered
with ClinicalTrials.gov, number NCT01287117. This project was funded by
Genentech, Inc. and Novartis Pharma AG. ASTERIA I Investigators: Denmark:
Carsten Bindslev-Jensen, Tonny Karlsmark; France: Jean-Jacques Grob, Ziad
Reguiai, Alain Taieb; Germany: Randolf Brehler, Thomas Hoelting, Marcus
Maurer, Franziska Rueff, Knutt Schaekel; Italy: Adriano Mari; Poland: Piotr
Kuna, Krystyna Obtulowicz, Ewa Trebas-Pietras, Jolanta Weglowska; Spain:
Ana Maria Gimenez Arnau, Esther Serra Baldrich; Turkey: Emel Bülbül Baskan;
US: Oral Alpan, Robert Chrzanowski, Pramila Daftary, Daniel Ein, Sandra M.
Gawchik, Pinkus Goldberg, Alan Goldsobel, Michael Kaplan, Alan Kaufman,
Adina Knight, Phillip E. Korenblat, Bobby Lanier, Miguel Lanz, Fu-Tong Liu,
Patricia Lugar, Michael Marcus, Donald McNeil, Isaac Melamed, Steven
Meltzer, Anthony Montanaro, Mark Moss, Thomas Murphy, Andrew Pedinoff,
Syed Rehman, David Riester, Ronald Saff, Sarbjit Saini, Joseph Shapiro, Dareen
Siri, David Skoner, Ricardo Tan, Kay Walker, Steven M. Weinstein, Hugh
Windom.
AUTHOR CONTRIBUTIONS
SSS, MM, SS, CB-J, MSB, JC, and KR participated in the design of the study.
SSS, CB-J, MM, J-JG, EBB, OA, and SS participated in patient accrual and data
collection. All authors analyzed and interpreted the data. MSB was the study
biostatistician responsible for the statistical analyses. All authors were members
of the writing group and participated in the development of the report, agreed
on the content, reviewed drafts, and approved the final version.
SUPPLEMENTARY MATERIAL
Supplementary material is linked to the online version of the paper at
http://www.nature.com/jid
SS Saini et al.
Efficacy and Safety of Omalizumab in CIU/CSU
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