Urticaria
Conditions
Brief summary
This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of subcutaneous (SC) omalizumab (Xolair) as an add-on therapy through 48 weeks for treatment of H1 antihistamine refractory chronic idiopathic urticaria (CIU). After completing an initial 24-week open-label treatment period with omalizumab 300 milligrams (mg) every 4 weeks (Q4W), participants responding to omalizumab will be randomized at a 3:2 ratio (omalizumab:placebo) to either continue omalizumab or be transitioned to placebo for a further 24 weeks.
Interventions
DRUGOmalizumab
Omalizumab 300 mg administered SC Q4W.
DRUGPlacebo
Placebo matched to omalizumab administered SC Q4W.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of CIU refractory to H1 antihistamines at baseline * Presence of itch and hives for at least 8 consecutive weeks at any time prior to enrollment despite current use of H1 antihistamine treatment (up to four times the approved dose) during this time period * UAS7 score (range 0-42) ≥ 16 and itch component of UAS7 (range 0-21) ≥ 8 during 7 days prior to baseline * Participants must have been on a non-sedating H1 antihistamine treatment (up to four times the approved dose) for CIU for at least 3 consecutive days immediately prior to screening visit with continued current use on the day of the initial screening visit * CIU diagnosis for ≥ 6 months * Willing and able to complete a daily symptom eDiary for the duration of the study
Exclusion criteria
* Treatment with an investigational agent within 30 days of the initial screening visit * Body weight less than 20 kilograms * Clearly defined underlying etiology for chronic urticarias other than CIU * Evidence of a parasitic infection * Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus or other skin disease associated with itch * Previous treatment with omalizumab within 1 year prior to the initial screening visit * Participants may not have taken during treatment period or have been taking within 30 days before the initial screening visit any of the following medications or treatments: regular (daily/every other day during 5 or more consecutive days) systemic corticosteroids, hydroxychloroquine, methotrexate, mycophenolate, cyclosporine, cyclophosphamide, intravenous immunoglobulin G or plasmapheresis * Regular (daily/every other day) oral doxepin use within 14 days prior to the initial screening visit * Pregnant or lactating women, or women intending to become pregnant during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Clinical Worsening in CIU as Assessed by Urticaria Activity Score Over 7 Days (UAS7) (Clinical Worsening: UAS7 Greater Than or Equal to [>/=] 12, Maintained for At Least 2 Consecutive Weeks) | From randomization (Week 24) to Week 48 | Urticaria activity score (UAS) is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals (hives) per 24 hours and the intensity of the pruritus (itch). The total UAS score (sum of the wheal and pruritus scores) ranges from 0 to 6. Due to variations in chronic urticaria disease intensity, assessment of disease activity was based on a weekly (7 days) UAS score called UAS7, that is, the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. Clinical worsening in CIU was defined as UAS7 \>/=12 for at least 2 consecutive weeks post-randomization between Weeks 24 and 48. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Worsening in CIU as Assessed by UAS7 (Clinical Worsening: UAS7 >/=12, Maintained for At Least 2 Consecutive Weeks) | From randomization (Week 24) to Week 48 | The UAS is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals per 24 hours and the intensity of the pruritus. The total UAS score ranges from 0 to 6. UAS7 is the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. Time to clinical worsening in CIU was defined as the number of weeks from the first double-blind treatment to the first two-week interval with UAS7 \>/=12 for both weeks. If clinical worsening did not occur, time to clinical worsening was censored at the end of the last week for which the UAS7 score was not missing and less than (\<) 12, prior to last randomized dose + 4 weeks, or the first open-label transition dose, whichever was earlier. Median time to clinical worsening was estimated using Kaplan-Meier analysis and corresponding 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley. |
| Percentage of Participants Who Experienced Clinical Worsening in CIU as Assessed by UAS7 (Clinical Worsening: UAS7 Greater Than [>] 6, Maintained for At Least 2 Consecutive Weeks) | From randomization (Week 24) to Week 48 | The UAS is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals per 24 hours and the intensity of the pruritus. The total UAS score ranges from 0 to 6. UAS7 is the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. Clinical worsening in CIU was defined as UAS7 \>6 for at least 2 consecutive weeks post-randomization between weeks 24 and 48. |
| Change From Randomization (Week 24) to Week 48 in UAS7 Among Participants Who Received Total 48 Weeks Treatment With Omalizumab | Week 24 (randomization) and Week 48 | The UAS is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals per 24 hours and the intensity of the pruritus. The total UAS score ranges from 0 to 6. UAS7 is the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. A negative change in score (Week 48 score minus Week 24 score) indicates improvement. |
| Retreatment Efficacy: Change From Time of Retreatment to 12 Weeks After Retreatment in UAS7 Among Participants Randomized to Placebo and Who Were Retreated With Open-Label Omalizumab After Randomization | At start of retreatment (any time between Weeks 24 and Week 48) and 12 weeks after retreatment (up to Week 60) | The UAS is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals per 24 hours and the intensity of the pruritus. The total UAS score ranges from 0 to 6. UAS7 is the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. A negative change in score indicates improvement. |
Countries
United States
Participant flow
Pre-assignment details
A total of 206 participants were enrolled in the study, but only 205 participants received at least one dose of any study treatment. Results include only the treated 205 participants.
Participants by arm
| Arm | Count |
|---|---|
| Omalizumab (Non-Randomized Participants) Participants received open-label omalizumab treatment at a dose of 300 mg via SC injection Q4W for 24 weeks. After Week 24, participants did not receive any treatment and only returned for a final follow-up visit (12 weeks after Week 24 visit). | 71 |
| Omalizumab (Randomized Participants) Participants received open-label omalizumab treatment at a dose of 300 mg via SC injection Q4W for 24 weeks. After 24 weeks of open-label treatment, participants received randomized treatment with omalizumab 300 mg via SC injection Q4W for a further 24 weeks (up to Week 48). Participants, at the discretion of the investigator, could have been transitioned from blinded study drug to open-label omalizumab at a dose of 300 mg via SC injection Q4W if they experienced clinically significant worsening in their CIU (as judged by the investigator). Participants who were transitioned to open-label omalizumab continued to receive open-label omalizumab until Week 48. | 81 |
| Placebo (Randomized Participants) Participants received open-label omalizumab treatment at a dose of 300 mg via SC injection Q4W for 24 weeks. After 24 weeks of open-label treatment, participants received randomized treatment with placebo matching to omalizumab via SC injection Q4W for a further 24 weeks (up to Week 48). Participants, at the discretion of the investigator, could have been transitioned from blinded study drug to open-label omalizumab at a dose of 300 mg via SC injection Q4W if they experienced clinically significant worsening in their CIU (as judged by the investigator). Participants who were transitioned to open-label omalizumab continued to receive open-label omalizumab until Week 48. | 53 |
| Total | 205 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 | 2 |
| Overall Study | Other | 49 | 1 | 1 |
| Overall Study | Pregnancy | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Sponsor/Investigator Decision | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 15 | 12 | 9 |
Baseline characteristics
| Characteristic | Total | Omalizumab (Non-Randomized Participants) | Placebo (Randomized Participants) | Omalizumab (Randomized Participants) |
|---|---|---|---|---|
| Age, Continuous | 44.6 years STANDARD_DEVIATION 14.46 | 43.5 years STANDARD_DEVIATION 14.76 | 48.5 years STANDARD_DEVIATION 13.22 | 43.1 years STANDARD_DEVIATION 14.68 |
| Race/Ethnicity, Customized Ethnicity: Hispanic or Latino | 43 participants | 20 participants | 5 participants | 18 participants |
| Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino | 161 participants | 50 participants | 48 participants | 63 participants |
| Race/Ethnicity, Customized Ethnicity: Unknown | 1 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Race: American Indian or Alaska Native | 2 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Race: Asian | 5 participants | 0 participants | 3 participants | 2 participants |
| Race/Ethnicity, Customized Race: Black or African American | 23 participants | 10 participants | 7 participants | 6 participants |
| Race/Ethnicity, Customized Race: Mixed/Unknown | 7 participants | 3 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Race: White | 168 participants | 58 participants | 42 participants | 68 participants |
| Sex: Female, Male Female | 153 Participants | 53 Participants | 40 Participants | 60 Participants |
| Sex: Female, Male Male | 52 Participants | 18 Participants | 13 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 71 | 0 / 81 | 0 / 53 |
| other Total, other adverse events | 22 / 71 | 28 / 81 | 22 / 53 |
| serious Total, serious adverse events | 0 / 71 | 2 / 81 | 3 / 53 |
Outcome results
Primary
Percentage of Participants Who Experienced Clinical Worsening in CIU as Assessed by Urticaria Activity Score Over 7 Days (UAS7) (Clinical Worsening: UAS7 Greater Than or Equal to [>/=] 12, Maintained for At Least 2 Consecutive Weeks)
Urticaria activity score (UAS) is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals (hives) per 24 hours and the intensity of the pruritus (itch). The total UAS score (sum of the wheal and pruritus scores) ranges from 0 to 6. Due to variations in chronic urticaria disease intensity, assessment of disease activity was based on a weekly (7 days) UAS score called UAS7, that is, the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. Clinical worsening in CIU was defined as UAS7 \>/=12 for at least 2 consecutive weeks post-randomization between Weeks 24 and 48.
Time frame: From randomization (Week 24) to Week 48
Population: Modified Intent-to-Treat (mITT) population included all randomized participants who received at least one dose of blinded study drug, and achieved one post-baseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omalizumab (Randomized Participants) | Percentage of Participants Who Experienced Clinical Worsening in CIU as Assessed by Urticaria Activity Score Over 7 Days (UAS7) (Clinical Worsening: UAS7 Greater Than or Equal to [>/=] 12, Maintained for At Least 2 Consecutive Weeks) | 21.0 percentage of participants |
| Placebo (Randomized Participants) | Percentage of Participants Who Experienced Clinical Worsening in CIU as Assessed by Urticaria Activity Score Over 7 Days (UAS7) (Clinical Worsening: UAS7 Greater Than or Equal to [>/=] 12, Maintained for At Least 2 Consecutive Weeks) | 60.4 percentage of participants |
Comparison: For participants who transitioned to open-label omalizumab, data prior to the date of transitioning was used for analysis.p-value: <0.000195% CI: [-54.5, -22.5]Chi-squared
Secondary
Change From Randomization (Week 24) to Week 48 in UAS7 Among Participants Who Received Total 48 Weeks Treatment With Omalizumab
The UAS is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals per 24 hours and the intensity of the pruritus. The total UAS score ranges from 0 to 6. UAS7 is the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. A negative change in score (Week 48 score minus Week 24 score) indicates improvement.
Time frame: Week 24 (randomization) and Week 48
Population: Analysis was performed on participants in mITT population who received total 48 weeks of treatment with omalizumab. If UAS7 data was missing, last observation carry forward (LOCF) method was used post-Week 24 for the closest non-missing UAS7 data up to Week 48.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omalizumab (Randomized Participants) | Change From Randomization (Week 24) to Week 48 in UAS7 Among Participants Who Received Total 48 Weeks Treatment With Omalizumab | Change at Week 48 | 1.77 units on a scale | Standard Deviation 6.47 |
| Omalizumab (Randomized Participants) | Change From Randomization (Week 24) to Week 48 in UAS7 Among Participants Who Received Total 48 Weeks Treatment With Omalizumab | Week 24 (Randomization) | 0.69 units on a scale | Standard Deviation 1.448 |
Comparison: The null hypothesis for this test was that the mean change from Week 24 to Week 48 in UAS7 score was \>/=5 and the alternative hypothesis was that the mean change from Week 24 to Week 48 in UAS7 score was \<5.p-value: <0.0001One-sample t-test, 1 sided
Secondary
Percentage of Participants Who Experienced Clinical Worsening in CIU as Assessed by UAS7 (Clinical Worsening: UAS7 Greater Than [>] 6, Maintained for At Least 2 Consecutive Weeks)
The UAS is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals per 24 hours and the intensity of the pruritus. The total UAS score ranges from 0 to 6. UAS7 is the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. Clinical worsening in CIU was defined as UAS7 \>6 for at least 2 consecutive weeks post-randomization between weeks 24 and 48.
Time frame: From randomization (Week 24) to Week 48
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omalizumab (Randomized Participants) | Percentage of Participants Who Experienced Clinical Worsening in CIU as Assessed by UAS7 (Clinical Worsening: UAS7 Greater Than [>] 6, Maintained for At Least 2 Consecutive Weeks) | 32.1 percentage of participants |
| Placebo (Randomized Participants) | Percentage of Participants Who Experienced Clinical Worsening in CIU as Assessed by UAS7 (Clinical Worsening: UAS7 Greater Than [>] 6, Maintained for At Least 2 Consecutive Weeks) | 64.2 percentage of participants |
Comparison: For participants who transitioned to open-label omalizumab, data prior to the date of transitioning was used for analysis.p-value: 0.000495% CI: [-47.9, -14.9]Chi-squared
Secondary
Retreatment Efficacy: Change From Time of Retreatment to 12 Weeks After Retreatment in UAS7 Among Participants Randomized to Placebo and Who Were Retreated With Open-Label Omalizumab After Randomization
The UAS is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals per 24 hours and the intensity of the pruritus. The total UAS score ranges from 0 to 6. UAS7 is the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. A negative change in score indicates improvement.
Time frame: At start of retreatment (any time between Weeks 24 and Week 48) and 12 weeks after retreatment (up to Week 60)
Population: Analysis was performed on participants in mITT population who were randomized to placebo arm and who were retreated with open-label omalizumab after randomization. Here, 'Number Analyzed' signifies number of participants with available data for this outcome at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omalizumab (Randomized Participants) | Retreatment Efficacy: Change From Time of Retreatment to 12 Weeks After Retreatment in UAS7 Among Participants Randomized to Placebo and Who Were Retreated With Open-Label Omalizumab After Randomization | UAS7 at the Time of Retreatment | 30.51 units on a scale | Standard Deviation 8.831 |
| Omalizumab (Randomized Participants) | Retreatment Efficacy: Change From Time of Retreatment to 12 Weeks After Retreatment in UAS7 Among Participants Randomized to Placebo and Who Were Retreated With Open-Label Omalizumab After Randomization | Change at 12 Weeks After Retreatment | -29.48 units on a scale | Standard Deviation 9.632 |
Comparison: The null hypothesis for this test was that the mean change from the time of retreatment to 12 weeks after retreatment in UAS7 was zero and the alternative hypothesis was that this change was non-zero.p-value: <0.0001One-sample t-test, 2 sided
Secondary
Time to Clinical Worsening in CIU as Assessed by UAS7 (Clinical Worsening: UAS7 >/=12, Maintained for At Least 2 Consecutive Weeks)
The UAS is a composite diary-recorded score with numeric severity ratings (0=none to 3=intense) for the number of wheals per 24 hours and the intensity of the pruritus. The total UAS score ranges from 0 to 6. UAS7 is the sum of the daily average UASs (average of morning and evening scores), ranging from 0 to 42 per week. A higher score indicates worse disease. Time to clinical worsening in CIU was defined as the number of weeks from the first double-blind treatment to the first two-week interval with UAS7 \>/=12 for both weeks. If clinical worsening did not occur, time to clinical worsening was censored at the end of the last week for which the UAS7 score was not missing and less than (\<) 12, prior to last randomized dose + 4 weeks, or the first open-label transition dose, whichever was earlier. Median time to clinical worsening was estimated using Kaplan-Meier analysis and corresponding 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley.
Time frame: From randomization (Week 24) to Week 48
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Omalizumab (Randomized Participants) | Time to Clinical Worsening in CIU as Assessed by UAS7 (Clinical Worsening: UAS7 >/=12, Maintained for At Least 2 Consecutive Weeks) | NA weeks |
| Placebo (Randomized Participants) | Time to Clinical Worsening in CIU as Assessed by UAS7 (Clinical Worsening: UAS7 >/=12, Maintained for At Least 2 Consecutive Weeks) | 12.0 weeks |
Comparison: For participants who transitioned to open-label omalizumab, data prior to the date of transitioning was used for analysis.p-value: <0.0001Log Rank