Table 2 Inclusion and exclusion criteria, number of eligible randomized studies, sample size, interventions and patients lost from included studies

1

Maurer et al., 2011 [20]

Moderade to severe CSU with persistent symptoms for ≥6 weeks in spite of treatment at maximum doses of antihistamines H1. UAS score >10 at the end of the test.

Acute urticaria, diarrhea, kidney failure, elevated IgE due to other allergy or urticaria reasons, epilepsy, antibiotic allergic reactions, malignancies in the last 5 years, CVA or ischemia, IV steroid use, methotrexate, cyclosporine or other immunosuppressant 4 weeks before

341

49

27

27 Omalizumab 75–375 mg dose according to weight, subcutaneous, once every 2 or 4 weeks for 24 weeks

H1 antihistamines, 10 mg of loratadine on demand and 1 mg of clemastine as rescue medication

24 weeks

-

2 (7.40)

22

Placebo

-

5 (22.72)

2

Saini et al., 2011 [21]

Idiopathic chronic urticaria, for more than 3 months, no definitive cause, moderate to severe symptoms, pruritus and urticaria for more than 3 days in 7 days for a period of 6 weeks in spite of treatment with antiH1. UAS ≥4 or UAS7 ≥ 12 during run-in period before randomization.

Weight <40 kg, pregnancy or lactation, other skin disorder associated to pruritus, treatment with omalizumab 12 months before, contraindication for diphenhydramine, treatment with any other investigational drug 30 days before, clinically relevant disease that could affect the outcomes, impairment to complete follow up, use of immunosuppresants 3 months before hydroxicloroquine, methotrexate, sulfasalazine, dapsone, cyclophosphamide, intravenous immunoglobulin, plasmapheresis, other therapies with monoclonal antibodies, use of cyclosporine in the month before, use of antileukotriens or antihistamines H2 the week before.

119

90

23

Omalizumab 75 mg single dose sc

All patients were provided 25 mg of diphenhydramine to use as a rescue medication for pruritus relief on an as-needed basis. The maximum allowable daily dose of diphenhydramine was 75 mg in the United States and 50 mg in Germany. Patients who required any other medications(including systemic corticosteroids) to treat persistent/worsening diseasewere discontinued from the study

4 weeks

12 weeks

5 (21.73)

25

Omalizumab 300 mg single dose sc

12 week

2 (8.0)

21

Omalizumab 600 mg single dose sc

12 weeks

1 (4.76)

21

Placebo1

12 weeks

1 (4.76)

3

Maurer et al., 2013 [19]

Idiopathic chronic urticaria for 6 months, presence of urticaria with pruritus for at least 8 consecutive weeks before inclusion in spite of consecutive use of antihistamines, UAS 7 ≥ 16 (range 0–42), weekly itch score < =8 (range 0–21) 7 days before randomization, without losses of electronic poll 7 days prior to randomization.

Cause of urticaria (physical), use of systemic glucocorticoids for 5 or more days, hydroxicloroquine, methotrexate, cyclosporine, cyclophosphamide, or intravenous immunoglobulin 30 days before. Use of antiH2 or leukotriens antagonists days before the visit (14 days prior randomization), use of antiH1 in higher doses than the allowed 3 days before the visit, previous history of cancer, weight < 20 kg, hypersensitivity to omalizumab, treatment with omalizumab in the previous year, pregnancy.

466

323

82

75 mg omalizumab, one injection every 4 weeks for 3 doses

Prerandomization H1-antihistamine throughout the treatment period. During the follow-up period, patients were permitted to use a licensed dose of one additional H1-antihistamine. For the duration of the study, all patients were provided with diphenhydramine (25 mg) as rescue medication for itch relief (up to a maximum of three doses in 24 hours on the basis of local regulations).

12 weeks

16 weeks

7 (8.53)

83

150 mg omalizumab, one injection every 4 weeks for 3 doses

16 weeks

9 (10.84)

79

300 mg omalizumab, one injection every 4 weeks for 3 doses

16 weeks

12 (15.18)

79

Placebo, similar presentation to drug

16 weeks

5 (6.32)

4

Kaplan et al., 2013 [22]

12 to 75 years old, 18–75 years in Germany, idiopathic chronic urticaria for 6 months or more, pruritus and hives for more than 6 weeks before inclusion in spite of antiH1, antiH2, antileukotriens or both, UAS7 ≥ 16 and an itchy index of 8 or more, 7 days before randomization, UAS at the clinic of 0 or more in one of the visits, treatment with antiH1, antiH2, antileukotriens or both regime, 3 consecutive days, 14 days before, patient desires to participate, signs informed consent, no loss of symptoms 3 days prior to randomization

Cause of urticaria (physical), daily systemic steroids doses more than 5 days, use of hydroxicloroquine, methotrexate, cyclosporine, cyclophosphamide, or intravenous immunoglobulin 30 days before, previous history of cancer, hypersensitivity to omalizumab in the previous year, evidence of parasitic infection, history of anaphylactic shock, pregnancy or lactation, potential pregnancy not accepting contraception

480

336

252

Omalizumab 300 mg every 4 weeks for doses

Maintain stable doses of their prerandomization combination therapy with H1-antihistamine treatment plus H2-antihistamines, LTRAs, or both. For the duration of the study, patients were provided with 25 mg of diphenhydramine as rescue medication for symptom relief (up to a maximum of 3 doses per 24-hour period or fewer depending on local regulations).

24 weeks

16 weeks

31 (12.3)

84

Placebo in the same presentation and administration

16 weeks

21 (25.0)

5

Saini et al., 2014 [23]

12-75 years old, (18–75 years in Germany), with diagnosis of CSU ≥ 6 months with hives and itching ≥8 consecutive weeks despite of anti H1 treatment. Use of an approved dosage of an H1 antihistamine for ≥3 consecutive days, UAS ≥ 4 on one or more screening days, UAS7 ≥ 16 an itch component of UAS7 ≥ 8 during the 7 days before randomization, willing to complete symptom diary, no missing eDiary entries during the 7 days before randomization

Clearly defined underlying etiology for chronic urticaria (cold, presure, etc.), presence of disease with symptoms of urticaria or angioedema, including hereditary or acquired angioedema, routine dosis of systemic steroids, hydroxychloroquine, methotrexate, cyclosporine, cyclophosphamide, or intravenous immunoglobulin ≤30 days of day −14. use of H2-antihistamines or LTRA ≤ 7 days of day −14. use of H1 antihistamines at greater than the approved doses ≤3 days of day −14. history of malignancy, weight <20 kg, hypersensitivity to omalizumab, previous treatment with omalizumab within the previous year.

483

319

78

Omalizumab 75 mg every 4 weeks for 6 doses

Maintain stable doses of their prerandomization H1 antihistamine treatment. Weeks 13 to 24 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)

24 weeks

16 weeks

11 (14.10)

80

omalizumab 150 mg every 4 weeks for 6 doses

16 weeks

16 (20.0)

81

omalizumab 300 mg every 4 weeks por 6 doses

16 weeks

8 (9.87)

80

placebo

16 weeks

19 (23.75)