As the first physiological line of defense and the largest organ, skin is always involved in the function of the body, maintaining the unity of opposites between the body and the natural environment, and the abnormal situation of the body can also be reflected on the skin surface. The skin has almost perfect physiological protective functions, such as barrier, sensory, body temperature regulation, absorption, secretion and excretion, the two of which play a very important role in maintaining the health of the body. The most common causes of skin diseases are infectious and allergic dermatitis. However, in addition to the degenerative changes of aging, senile dermatosis, skin cancer and other important skin diseases, attention should also be paid to various skin disorders caused by side effects associaed with drug therapy.
Skin diseases can be classified into viral skin diseases, bacterial skin diseases, allergic and autoimmune skin diseases according to the cause of the disease. Urticaria is a localized edema reaction caused by increasing the permeability of the small blood vessels in the skin and mucous membranes. The basic symptom is the wind group on the skin. Usually, the skin is itchy first, then followed by a wheal of bright red or pale skin color. A small number of patients have edematous erythema. The size and shape of the wind group are different, and the onset time is uncertain. Some patients may be accompanied by nausea, vomiting, headache, head swelling, abdominal pain, diarrhea, and severe patients may also have chest tightness, discomfort, pale, heart rate, pulse weakness, elevated blood pressure, and systemic symptoms.
Chronic idiopathic urticaria (also called chronic spontaneous urticaria) is defined as itchy hives that last for at least 6 weeks, with or without angioedema, and that have no apparent external trigger. The condition generally has a prolonged duration of 1 to 5 years (persisting for >5 years in 11 to 14% of patients) and has a detrimental effect on patients’ emotional and physical health-related quality of life. As the current mainstay for initial treatment, H1 antihistamines are the only agents licensed for use in patients with chronic idiopathic urticaria. However, a majority of patients do not have a response to H1 antihistamines, even when the drugs are administered at three to four times their licensed dose.
Here we report the results of a phase 3 clinical trial in patients with chronic idiopathic urticaria in which we evaluated the effects of three doses of omalizumab as compared with placebo.
In most clinical trials, the recruitment of patients is often the primary difficulty. In order to obtain reliable and statistically significant experimental data, researchers need patients aged 12 to 75 who met all the following criteria: a history of at least 6 months of chronic idiopathic urticaria, the presence of hives associated with itching for at least 8 consecutive weeks, an urticaria activity score (UAS) of 9.5 to 10.5 during 7-day period (UAS7) of 16 or more), a weekly itch-severity score of 8 or more during the 7 days before randomization (week 0), a score of 4 or more on the UAS.
In clinical studies, the outcome of clinical research is one of the research design elements, and the study endpoints can directly assess the efficacy of the study. The endpoints must be objective and have established criteria for judgment, such as cure, relief, effectiveness, or survival, etc. In this study, the primary endpoint was the change from baseline to week 12 in the weekly itch-severity scores. The 12-week score was calculated as the sum of the averaged daily itch-severity score for the previous 7 days, and the baseline score was the sum of the daily itch-severity scores during the 7 days before randomization. Secondary endpoints, which were all evaluated at week 12, were changes from baseline in the UAS7 and in the score for the weekly number of hives, the time until a reduction from baseline of at least 5 points in the weekly itch-severity score (the MID), the proportions of patients with a UAS7 of 6 or less (considered to represent improvement in disease), the number of patients with a weekly MID response in the itch-severity score, the change from baseline in the score for the size of the largest hive, the change from baseline in the overall score on the Dermatology Life Quality Index, and the proportion of angioedema-free days from week 4 to week 12.
Another challenge in clinical trials is the statistical analysis of data. The statistical methods used in clinical trials must be carefully selected based on the data. In estimating the power of determining efficacy, we assumed a mean change from baseline to week 12 in the weekly itch-severity score of 9 points in the omalizumab group and a mean change of 3.5 points in the placebo group, with a common standard deviation of 6 points. Assuming an early discontinuation rate of 15% by week 12, we determined that the enrollment of 300 patients (75 patients in each treatment group) would yield a power of approximately 98% to detect a difference in treatment effect in the primary endpoint at the 0.05 level for any omalizumab group. For the primary endpoint, we analyzed differences between each of the omalizumab treatment groups and the placebo group by using an analysis-of-covariance model stratified according to the estimated baseline weekly itch-severity score (<13 vs. ≥13) and baseline weight (<80 kg vs.≥80 kg). The strata were predefined on the basis of the medians reported in a phase 2 clinical study. Missing data at week 12 were imputed with the baseline score (baseline observation carried forward).
Using the above strategy, we recruited appropriate patients to evaluate the effects of three doses of omalizumab as compared with placebo.
In this international, multicenter, randomized, double-blind and placebo-controlled study, we selected the doses for this study based on the results of a previous phase 2 dose-ranging study. Doses were administered at 4-week intervals, so as to ensure that the blinding was maintained. Each of the doses was administered by a qualified designated clinician who was not involved in the evaluation of the patients’ symptoms. This 12-week treatment period was followed by a 16 week follow-up period (for further details, see the Supplementary Appendix, available with the full text of this article at NEJM.org). Patients used an electronic handheld device to self-record data about validated urticaria.
We investigated the efficacy and safety of omalizumab over 28 weeks in adult and adolescent (≥12 years) patients with chronic idiopathic urticaria who had remained symptomatic despite the use of approved doses of H1 antihistamines.
Length of Enrollment Period:
Eligible patients were stratified according to smoking status and then randomized to receive either roflumilast (500 μg) or placebo once daily. A single-blind 4-week run-in period was followed by a double-blind 12-week treatment period.
- The itch-severity score
- The number of hives
- Scores for the size of the largest hive
- Interference with sleep and daily activities
- Average daily scores for itch severity
Baseline demographic and clinical characteristics were similar across the study groups (Table1). For the overall population, the mean (±SD) age was 42.5±13.7, women occupied 76% of patients, 85% were white, the mean body weight was 82.4±21.9 kg, and the mean body mass index (the weight in kilograms divided by the square of the height in meters) was 29.8±7.3. The mean in clinical UAS was 5.3±0.7, the mean UAS7 was 30.7±6.8, the weekly itch severity score was 14.0±3.7, the weekly score for the number of hives was 16.7±4.3 and the dose of rescue medications was 7.3±7.8 tablets per week. Angioedema was present in 41% of patients during the week before randomization.
Table 1. Baseline characteristics of the patients (modified intention to treat population) *.
* Plus-minus values are means ±SD. The modified intention to treat population included all patients who had undergone randomization and received at least one dose of a study drug. There were no significant differences among the groups at baseline. Percentages may not total 100 because of rounding.
† Race was self-reported.
‡ The body mass index is the weight in kilograms divided by the square of the height in meters.
§ Data are for 77 patients in the placebo group, 80 in the group assigned to receive 75 mg of omalizumab, 81 in the group assigned to receive 150 mg of omalizumab, and 76 in the group assigned to receive 300 mg of omalizumab.
¶ The urticaria activity score (UAS) ranges from 0 to 6, with higher scores indicating greater activity. This value was defined as the largest value among those obtained on screening visits on days 14 and 7 before randomization and on the day 1 visit.
‖ The UAS during a 7 day period (UAS7) ranges from 0 to 42, with higher scores indicating greater activity and a minimally important difference (MID) of 9.5 to 10.5.
** These values are based on data that were collected in a patients’ daily diary in the week before randomization.
†† Daily scores for itch severity were 0 indicating none, 1 indicating mild, 2 indicating moderate, and 3 indicating severe, with weekly totals ranging from 0 to 21 and an MID of 5 or more points.
‡‡ Daily scores for the number of hives were 0 indicating none, 1 indicating 1 to 6, 2 indicating 7 to 12, and 3 indicating≥12, and an MID of 5.0 to 5.5 for the weekly average.
§§ The Dermatology Life Quality Index ranges from 0 to 30, with higher scores indicating a worse quality of life and an MID of 2.24 to 3.10.
¶¶ This value was measured in 78 patients in the placebo group.
Baseline weekly itch severity scores were approximately 14 in all treatment groups (Table 1). The mean changes from baseline in weekly itch severity scores at week 12 (primary endpoint) were significantly improved in the group receiving 150 mg of omalizumab (–8.1±6.4, P=0.001) and 300 mg of omalizumab (–9.8±6.0, P<0.001) but not in the group receiving 75 mg of omalizumab (–5.9±6.5, P= 0.46), as compared with the placebo group(–5.1±5.6) (Table 2). The reductions from baseline in mean weekly itch severity scores were dose responsive with all three omalizumab doses and were better than the placebo responses at the time points before week 12 (Figure 1A). After week 12 (follow-up period), the mean weekly itch severity scores for all omalizumab groups increased to reach values similar to those in the placebo group and did not return to baseline values for the duration of follow-up. Similar to weekly itch severity scores, the weekly score for the number of hives decreased with all three doses of omalizumab to a greater extent than with the placebo group throughout the 12-week treatment period, with the largest difference observed in the 300 mg group (Figure 1B).
Table 2. Primary and secondary efficacy endpoints (modified intention to treat population) *.
* Plus-minus values are means ±SD. Missing scores for week 12 were imputed from baseline weekly scores. NA denotes “not applicable.”
† Least squares means were estimated with the use of an analysis of covariance (ANCOVA) model stratified according to the baseline weekly itch severity score (<13 vs. ≥13) and baseline weight (<80 kg vs. ≥80 kg).
‡ P<0.01 for the comparison with placebo.
§ P<0.001 for the comparison with placebo.
¶ The ANCOVA model was stratified according to the baseline weekly number of hives (<median vs. ≥median) and baseline weight (<80 kg vs. ≥80 kg).
‖ The baseline score on the Dermatology Life Quality Index was obtained before administration of a study drug on day 1, and there was no imputation for missing scores for week 12.
** The ANCOVA model was stratified according to the baseline overall score on the Dermatology Life Quality Index (<median vs. ≥median) and baseline weight (<80 kg vs. ≥80 kg).
†† P = 0.02 for the comparison with placebo.
‡‡ Angioedema free days were defined as the number of days for which the patient responded “no” to the angioedema question in the daily diary divided by the total number of days with a no missing diary entry starting at the week 4 visit and ending at the day before the week 12 visit. Patients who withdrew before the week 4 visit or who had missing responses for more than 40% of the daily diary entries between the week 4 and week 12 study visits were not included in this analysis.
Figure 1. Mean weekly symptom scores.
The percentages of patients with at least one adverse event were similar across the treatment groups: 61% in the placebo group, 59% in those receiving 75 mg of omalizumab, 67% in those receiving 150 mg of omalizumab, and 65% in those receiving 300 mg of omalizumab (Table 3). During the 28-week study period, there were reports of nine serious adverse events, with five reported in the group receiving 300 mg of omalizumab (6%), two in the placebo group (3%), and one each in the groups receiving 75 mg and 150 mg of omalizumab (1% for each). Most of the adverse events were reported in the 150mg and 300mg groups during the follow-up period, when no drug was being administered (Table 3). No deaths or episodes of anaphylactic shock were reported during the study. There were no major imbalances in any of the system organ classes affected by adverse events, with the exception of a headache, with more cases being reported in the group receiving 150 mg of omalizumab than in the placebo group.
Table 3. Adverse events (safety population) *.
* The safety population was defined according to the treatment actually received.
‡ A severe adverse event was defined as the occurrence of symptoms causing an inability to perform usual social and functional activities. A complete description of the severe adverse events is provided in the Safety section in the Supplementary Appendix.
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1. Hiragun, M., Hiragun, T., Mihara, S., Akita, T., Tanaka, J., & Hide, M. (2013) ‘Prognosis of chronic spontaneous urticaria in 117 patients not controlled by a standard dose of antihistamine’, Allergy, 68(2), 229-235.
2. Duarte, F. C., Costa, A. C., Silva, S. L. D., Lopes, A., Santos, A. S., & Pedro, E., et al. (2010) ‘Evaluating immunoglobulin treatment in autoimmune chronic urticaria’,Revista Portuguesa De Imunoalergologia, 18(2), 137-156.
3. Marciniak, A., Wegner, J., Czarnecka-Operacz, M., & Jenerowicz, D. (2006) ‘The problem of eosinophilia in chronic urticaria’, Postepy Dermatologii I Alergologii, 23(1), 5-11.