Chronic Spontaneous Urticaria
Conditions
Keywords
Chronic spontaneous urticaria, ISS7, UAS7, omalizumab, China
Brief summary
The purpose of this study was to demonstrate the efficacy and safety of omalizumab, compared with placebo, as an add-on to H1 antihistamines (H1AH) therapy in adult patients suffering from Chronic Spontaneous Urticaria (CSU) who remained symptomatic despite H1AH therapy.
Detailed description
This was a randomized, multicenteric, double-blinded, placebo-controlled, parallel-group study to evaluate the efficacy and safety of omalizumab as an add-on therapy for the treatment of patients of refractory CSU who remained symptomatic despite approved-dosed H1AH treatment. The study consisted of three distinct epochs over 24 weeks: Screening epoch (Day -28 to Day -1), Randomized treatment epoch (Day 1 to Week 12) and Post-treatment follow-up epoch (Week 12 to Week 20). Patients were randomized into three treatment groups (omalizumab 300 mg s.c. omalizumab 150 mg s.c. and placebo) in a 2:2:1 ratio, stratified by latent tuberculosis (TB) status at Baseline (Yes/No). On Day 1, eligible patients were randomly assigned to receive omalizumab (150 mg or 300 mg) or placebo by subcutaneous (s.c.) injection every 4 weeks (on Day 1, Week 4, and Week 8) during the 12-week double-blind randomized-treatment epoch. Patients visited the study center at 4-week intervals. Patients were instructed to stay on the same CSU H1AH treatment at stable dose that they were using during the pre-randomization period during the randomized treatment epoch. They were allowed to use diphenhydramine as rescue medication during all epochs. The last dose of the study drug during the randomized-treatment epoch was administered at Week 8 study visit, however, the last assessment was done at Week 12. After the completion of the 12-week randomized-treatment epoch, all patients entered an 8-week post-treatment follow-up epoch.
Interventions
DRUGOmalizumab
injection of 150mg or 300 mg
DRUGPlacebo
Injection of placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Symptomatic CSU patients with CSU diagnosis for at least 6 months. * Patients must have been on an approved dose of an H1AH for CSU for at least the 3 consecutive days immediately prior to the Day -14 screening visit * Patients must have documented current use on the day of the initial screening visit Main
Exclusion criteria
* Clearly defined underlying etiology for chronic urticarias other than CSU (main manifestation being physical urticaria) * Other skin disease associated with itch Urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, or generalized cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of the Itch Severity Score (ISS7) Score After 12 Weeks of Treatment | Baseline, Week 12 | The severity of the itch was recorded by the patient twice daily in their eDiary, on a scale of 0 (none) to 3 (intense/severe). Baseline ISS7 was calculated 7 days prior to the first treatment date. A weekly score (ISS7) was derived by adding up the average daily scores of the seven days preceding the visit. The possible range of the weekly score was therefore 0 to 21, where 0 is the best score and 21 is the worst score. The complete itch response was defined as ISS7 = 0. Itch (Pruritus) Severity Score Scale: 0 = None 1. = Mild (minimal awareness, easily tolerated) 2. = Moderate (definite awareness, bothersome but tolerable) 3. = Severe (difficult to tolerate) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of Number of Hives Score (NHS7) After 12 Weeks of Treatment | Baseline, Week 12 | Hives Severity Score (HSS), defined by number of hives, were recorded by the patient twice daily in their eDiary, on a scale of 0 (none) to 3 (intense/severe). A weekly number of hives score (NHS7) was derived by adding up the average daily scores of the seven days preceding the visit. The possible range of the weekly score was therefore 0 to 21. The complete hives response was defined as NHS7 = 0. Hives Severity Score scale: 0 - None * Mild (1-6 hives/12 hours) * Moderate (7-12 hives/12 hours) * Severe (\>12 hives/12 hours) |
| Percentage of Patients With UAS7≤6 at Week 12 | Week 12 | UAS7 is the sum of the HSS7 and the ISS7 scores. The possible range of the weekly UAS7 score is 0 to 42. A higher urticaria activity score indicates more severe symptoms. A negative change score from baseline indicates improvement. Week 12 responders were defined as patients who achieved an absolute UAS7 ≤ 6 at Week 12. A patient with missing data at Week 12 was imputed as a responder if the patient was a responder at Week 10 and Week 11, otherwise as a non-responder. |
| Percentage of Complete Responders (UAS7 = 0) at Week 12 | Week 12 | UAS7 is the sum of the HSS7 and the ISS7 scores. The possible range of the weekly UAS7 score is 0 to 42. A higher urticaria activity score indicates more severe symptoms. A negative change score from baseline indicates improvement. Complete responders are defined as participants who achieved UAS7 = 0. |
| Change From Baseline of Urticaria Activity Score (UAS7) After 12 Weeks of Treatment | Baseline, Week 12 | UAS7 is the sum of the HSS7 and the ISS7 scores. The possible range of the weekly UAS7 score is 0 to 42. A higher urticaria activity score indicates more severe symptoms. A negative change score from baseline indicates improvement. |
| Change From Baseline of Dermatology Life Quality Index (DLQI) Score After 12 Weeks of Treatment | Week 12 | Dermatology life quality index (DLQI) is a 10-item dermatology- specific health-related quality of life measure. Patients rated their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives. An overall score was calculated as well as separate scores for the following domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, treatment. Each domain had 4 response categories ranging from 0 (not at all) to 3 (very much). Not relevant is a valid score also and is scored as 0. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment. |
| Time to ISS7 MID Response by Week 12 | 12 weeks | The ISS7 MID response was defined as a reduction from Baseline in ISS7 of ≥ 5 points. Time to ISS7 MID response was the time (in weeks) from the date of the first dose to the date where ISS7 MID response was first achieved during Week 1 to Week 12. |
| Percentage of Patients With ISS7 Minimally Important Difference (MID) at Week 12 | Week 12 | The severity of the itch was recorded by the patient twice daily in their eDiary, on a scale of 0 (none) to 3 (intense/severe). Baseline ISS7 was calculated 7 days prior to the first treatment date. A weekly score (ISS7) was derived by adding up the average daily scores of the seven days preceding the visit. The possible range of the weekly score was therefore 0 to 21, where 0 is the best score and 21 is the worst score. The complete itch response was defined as ISS7 = 0. Itch (Pruritus) Severity Score Scale: 0 = None 1. = Mild (minimal awareness, easily tolerated) 2. = Moderate (definite awareness, bothersome but tolerable) 3. = Severe (difficult to tolerate) The ISS7 MID response was defined as a reduction from Baseline in ISS7 of ≥ 5 points. |
Countries
China
Participant flow
Recruitment details
Patients were recruited from 27 sites across China.
Pre-assignment details
Patients were randomized into three treatment groups (omalizumab 300 mg s.c., omalizumab 150 mg s.c. and placebo) in a 2:2:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Omalizumab 300mg patients received a dose of omalizumab 300 mg which consisted of two injections of omalizumab 150 mg vials every 4 weeks (Day 1, Week 4 and Week 8) | 168 |
| Omalizumab 150mg patients received a dose of omalizumab 150 mg which consisted of one injection of omalizumab 150 mg vial and one injection of placebo 150 mg vial every 4 weeks (Day 1, Week 4 and Week 8) | 167 |
| Placebo patients received placebo which consisted of two injections of placebo 150 mg vials every 4 weeks (Day 1, Week 4 and Week 8) | 83 |
| Total | 418 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Follow-up Epoch | Adverse Event | 4 | 0 | 1 |
| Follow-up Epoch | Lack of Efficacy | 1 | 1 | 1 |
| Follow-up Epoch | Lost to Follow-up | 0 | 1 | 0 |
| Follow-up Epoch | Patient/guardian decision | 2 | 1 | 0 |
| Follow-up Epoch | Pregnancy | 1 | 0 | 0 |
| Randomized-treatment Epoch | Adverse Event | 4 | 1 | 1 |
| Randomized-treatment Epoch | Lack of Efficacy | 1 | 0 | 0 |
| Randomized-treatment Epoch | Lost to Follow-up | 0 | 1 | 0 |
| Randomized-treatment Epoch | Patient/guardian decision | 8 | 3 | 1 |
| Randomized-treatment Epoch | Pregnancy | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Omalizumab 300mg | Omalizumab 150mg |
|---|---|---|---|---|
| Age, Continuous | 42.8 years STANDARD_DEVIATION 12.32 | 40.2 years STANDARD_DEVIATION 12.31 | 40.4 years STANDARD_DEVIATION 12.29 | 38.8 years STANDARD_DEVIATION 12.18 |
| Race/Ethnicity, Customized Ethnicity Chinese | 83 Participants | 418 Participants | 168 Participants | 167 Participants |
| Race/Ethnicity, Customized Race Asian | 83 Participants | 418 Participants | 168 Participants | 167 Participants |
| Sex: Female, Male Female | 53 Participants | 276 Participants | 115 Participants | 108 Participants |
| Sex: Female, Male Male | 30 Participants | 142 Participants | 53 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 167 | 0 / 167 | 0 / 83 |
| other Total, other adverse events | 84 / 167 | 79 / 167 | 43 / 83 |
| serious Total, serious adverse events | 5 / 167 | 5 / 167 | 3 / 83 |
Outcome results
Primary
Change From Baseline of the Itch Severity Score (ISS7) Score After 12 Weeks of Treatment
The severity of the itch was recorded by the patient twice daily in their eDiary, on a scale of 0 (none) to 3 (intense/severe). Baseline ISS7 was calculated 7 days prior to the first treatment date. A weekly score (ISS7) was derived by adding up the average daily scores of the seven days preceding the visit. The possible range of the weekly score was therefore 0 to 21, where 0 is the best score and 21 is the worst score. The complete itch response was defined as ISS7 = 0. Itch (Pruritus) Severity Score Scale: 0 = None 1. = Mild (minimal awareness, easily tolerated) 2. = Moderate (definite awareness, bothersome but tolerable) 3. = Severe (difficult to tolerate)
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Omalizumab 300mg | Change From Baseline of the Itch Severity Score (ISS7) Score After 12 Weeks of Treatment | -10.11 Score on a scale | Standard Error 0.43 |
| Omalizumab 150mg | Change From Baseline of the Itch Severity Score (ISS7) Score After 12 Weeks of Treatment | -9.66 Score on a scale | Standard Error 0.424 |
| Placebo | Change From Baseline of the Itch Severity Score (ISS7) Score After 12 Weeks of Treatment | -5.87 Score on a scale | Standard Error 0.604 |
p-value: <0.00195% CI: [-5.7, -2.77]Mixed Model with Repeated Measures(MMRM)
p-value: <0.00195% CI: [-5.24, -2.33]Mixed Model with Repeated Measures(MMRM)
Secondary
Change From Baseline of Dermatology Life Quality Index (DLQI) Score After 12 Weeks of Treatment
Dermatology life quality index (DLQI) is a 10-item dermatology- specific health-related quality of life measure. Patients rated their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives. An overall score was calculated as well as separate scores for the following domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, treatment. Each domain had 4 response categories ranging from 0 (not at all) to 3 (very much). Not relevant is a valid score also and is scored as 0. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment.
Time frame: Week 12
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Omalizumab 300mg | Change From Baseline of Dermatology Life Quality Index (DLQI) Score After 12 Weeks of Treatment | -10.4 Score on a scale | Standard Error 0.5 |
| Omalizumab 150mg | Change From Baseline of Dermatology Life Quality Index (DLQI) Score After 12 Weeks of Treatment | -9.9 Score on a scale | Standard Error 0.49 |
| Placebo | Change From Baseline of Dermatology Life Quality Index (DLQI) Score After 12 Weeks of Treatment | -6.5 Score on a scale | Standard Error 0.69 |
p-value: <0.00195% CI: [-5.7, -2.3]Mixed Model with Repeated Measures(MMRM)
p-value: <0.00195% CI: [-5.1, -1.8]Mixed Model with Repeated Measures(MMRM)
Secondary
Change From Baseline of Number of Hives Score (NHS7) After 12 Weeks of Treatment
Hives Severity Score (HSS), defined by number of hives, were recorded by the patient twice daily in their eDiary, on a scale of 0 (none) to 3 (intense/severe). A weekly number of hives score (NHS7) was derived by adding up the average daily scores of the seven days preceding the visit. The possible range of the weekly score was therefore 0 to 21. The complete hives response was defined as NHS7 = 0. Hives Severity Score scale: 0 - None * Mild (1-6 hives/12 hours) * Moderate (7-12 hives/12 hours) * Severe (\>12 hives/12 hours)
Time frame: Baseline, Week 12
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Omalizumab 300mg | Change From Baseline of Number of Hives Score (NHS7) After 12 Weeks of Treatment | -11.68 Score on a scale | Standard Error 0.492 |
| Omalizumab 150mg | Change From Baseline of Number of Hives Score (NHS7) After 12 Weeks of Treatment | -11.11 Score on a scale | Standard Error 0.485 |
| Placebo | Change From Baseline of Number of Hives Score (NHS7) After 12 Weeks of Treatment | -5.76 Score on a scale | Standard Error 0.69 |
p-value: <0.00195% CI: [-7.59, -4.24]Mixed Model with Repeated Measures(MMRM)
p-value: <0.00195% CI: [-7, -3.69]Mixed Model with Repeated Measures(MMRM)
Secondary
Change From Baseline of Urticaria Activity Score (UAS7) After 12 Weeks of Treatment
UAS7 is the sum of the HSS7 and the ISS7 scores. The possible range of the weekly UAS7 score is 0 to 42. A higher urticaria activity score indicates more severe symptoms. A negative change score from baseline indicates improvement.
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Omalizumab 300mg | Change From Baseline of Urticaria Activity Score (UAS7) After 12 Weeks of Treatment | -21.82 Score on a scale | Standard Error 0.895 |
| Omalizumab 150mg | Change From Baseline of Urticaria Activity Score (UAS7) After 12 Weeks of Treatment | -20.74 Score on a scale | Standard Error 0.882 |
| Placebo | Change From Baseline of Urticaria Activity Score (UAS7) After 12 Weeks of Treatment | -11.62 Score on a scale | Standard Error 1.258 |
p-value: <0.00195% CI: [-13.25, -7.14]Mixed Model with Repeated Measures(MMRM)
p-value: <0.00195% CI: [-12.14, -6.1]Mixed Model with Repeated Measures(MMRM)
Secondary
Percentage of Complete Responders (UAS7 = 0) at Week 12
UAS7 is the sum of the HSS7 and the ISS7 scores. The possible range of the weekly UAS7 score is 0 to 42. A higher urticaria activity score indicates more severe symptoms. A negative change score from baseline indicates improvement. Complete responders are defined as participants who achieved UAS7 = 0.
Time frame: Week 12
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omalizumab 300mg | Percentage of Complete Responders (UAS7 = 0) at Week 12 | 62 Participants |
| Omalizumab 150mg | Percentage of Complete Responders (UAS7 = 0) at Week 12 | 39 Participants |
| Placebo | Percentage of Complete Responders (UAS7 = 0) at Week 12 | 4 Participants |
p-value: <0.00195% CI: [3.88, 32.37]Regression, Logistic
p-value: 0.00195% CI: [2.01, 17.17]Regression, Logistic
Secondary
Percentage of Patients With ISS7 Minimally Important Difference (MID) at Week 12
The severity of the itch was recorded by the patient twice daily in their eDiary, on a scale of 0 (none) to 3 (intense/severe). Baseline ISS7 was calculated 7 days prior to the first treatment date. A weekly score (ISS7) was derived by adding up the average daily scores of the seven days preceding the visit. The possible range of the weekly score was therefore 0 to 21, where 0 is the best score and 21 is the worst score. The complete itch response was defined as ISS7 = 0. Itch (Pruritus) Severity Score Scale: 0 = None 1. = Mild (minimal awareness, easily tolerated) 2. = Moderate (definite awareness, bothersome but tolerable) 3. = Severe (difficult to tolerate) The ISS7 MID response was defined as a reduction from Baseline in ISS7 of ≥ 5 points.
Time frame: Week 12
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omalizumab 300mg | Percentage of Patients With ISS7 Minimally Important Difference (MID) at Week 12 | 125 Participants |
| Omalizumab 150mg | Percentage of Patients With ISS7 Minimally Important Difference (MID) at Week 12 | 125 Participants |
| Placebo | Percentage of Patients With ISS7 Minimally Important Difference (MID) at Week 12 | 49 Participants |
p-value: <0.00195% CI: [1.51, 4.95]Regression, Logistic
p-value: 0.00295% CI: [1.41, 4.56]Regression, Logistic
Secondary
Percentage of Patients With UAS7≤6 at Week 12
UAS7 is the sum of the HSS7 and the ISS7 scores. The possible range of the weekly UAS7 score is 0 to 42. A higher urticaria activity score indicates more severe symptoms. A negative change score from baseline indicates improvement. Week 12 responders were defined as patients who achieved an absolute UAS7 ≤ 6 at Week 12. A patient with missing data at Week 12 was imputed as a responder if the patient was a responder at Week 10 and Week 11, otherwise as a non-responder.
Time frame: Week 12
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omalizumab 300mg | Percentage of Patients With UAS7≤6 at Week 12 | 81 Participants |
| Omalizumab 150mg | Percentage of Patients With UAS7≤6 at Week 12 | 79 Participants |
| Placebo | Percentage of Patients With UAS7≤6 at Week 12 | 9 Participants |
p-value: <0.00195% CI: [3.27, 15.06]Regression, Logistic
p-value: <0.00195% CI: [3.29, 15.06]Regression, Logistic
Secondary
Time to ISS7 MID Response by Week 12
The ISS7 MID response was defined as a reduction from Baseline in ISS7 of ≥ 5 points. Time to ISS7 MID response was the time (in weeks) from the date of the first dose to the date where ISS7 MID response was first achieved during Week 1 to Week 12.
Time frame: 12 weeks
Population: Full analysis set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Omalizumab 300mg | Time to ISS7 MID Response by Week 12 | First Response: >0 to <=4 weeks | 114 Participants |
| Omalizumab 300mg | Time to ISS7 MID Response by Week 12 | First Response: >4 to <=8 weeks | 18 Participants |
| Omalizumab 300mg | Time to ISS7 MID Response by Week 12 | First Response: >8 to <=12 weeks | 10 Participants |
| Omalizumab 300mg | Time to ISS7 MID Response by Week 12 | No response | 25 Participants |
| Omalizumab 150mg | Time to ISS7 MID Response by Week 12 | No response | 23 Participants |
| Omalizumab 150mg | Time to ISS7 MID Response by Week 12 | First Response: >0 to <=4 weeks | 109 Participants |
| Omalizumab 150mg | Time to ISS7 MID Response by Week 12 | First Response: >8 to <=12 weeks | 10 Participants |
| Omalizumab 150mg | Time to ISS7 MID Response by Week 12 | First Response: >4 to <=8 weeks | 25 Participants |
| Placebo | Time to ISS7 MID Response by Week 12 | No response | 24 Participants |
| Placebo | Time to ISS7 MID Response by Week 12 | First Response: >4 to <=8 weeks | 10 Participants |
| Placebo | Time to ISS7 MID Response by Week 12 | First Response: >8 to <=12 weeks | 7 Participants |
| Placebo | Time to ISS7 MID Response by Week 12 | First Response: >0 to <=4 weeks | 42 Participants |
p-value: <0.00195% CI: [1.25, 2.33]Regression, Cox
p-value: 0.00195% CI: [1.22, 2.25]Regression, Cox