Study of Efficacy and Safety of Ligelizumab in Chronic Spontaneous Urticaria Patients Who Completed a Previous Study With Ligelizumab

Study Overview
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Brief Summary
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The purpose of this extension study was to establish efficacy and safety of ligelizumab. This was assessed in adult and adolescent chronic spontaneous urticaria (CSU) patients who had completed a preceding ligelizumab study and have relapsed, following treatment in these preceding studies, despite standard of care H1-antihistamine (H1-AH) treatment. This study also fulfilled the Novartis commitment to provide post-trial access to patients who had completed studies: CQGE031C2302 (NCT03580369), CQGE031C2303 (NCT03580356), CQGE031C2202 (NCT03437278) or CQGE031C1301 (NCT03907878).

Detailed Description
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This was a Phase IIIb multi-center, double-blinded and open-label extension study to evaluate efficacy and safety of ligelizumab retreatment with H1-AHs background therapy with an option for ligelizumab monotherapy (i.e., discontinuation of background H1-AH) in adult and adolescent CSU participants who had completed one of the preceding studies, in the setting of retreatment and self-administration. Participants with weekly urticaria activity score (UAS7) < 16 during screening entered the first (investigational treatment-free) observation period (OBS1), with a duration up to 36 weeks. Participants with UAS7 ≥ 16 during screening or OBS1 were assigned to 1 of the 2 treatment arms and entered the treatment period (first half treatment period, referred to as TRT1). The first half treatment period (TRT1) was 52 weeks (from Week 0 to Week 52). Participants remained on the same H1-AH background medication they were taking in the preceding studies. TRT1 was divided into: The first 12 weeks in TRT1: i. participants transitioning from CQGE031C2302 (NCT03580369) and CQGE031C2303 (NCT03580356) previously treated with ligelizumab 72 mg liquid in vial subcutaneously (s.c.) every 4 weeks (Q4W) were treated with the same dose regimen in a double-blind manner in this extension study; ii. all other participants transitioning from CQGE031C2302 (NCT03580369) and CQGE031C2303 (NCT03580356) were treated with ligelizumab 120 mg liquid in vial s.c., Q4W, in a double-blind manner in this extension study; iii. participants transitioning from CQGE031C1301 (NCT03907878) and CQGE031C2202 (NCT03437278) were treated with ligelizumab 120 mg liquid in vial s.c., Q4W in an open-label manner in this extension study. After the first 12 weeks in TRT1 (and up to Week 52), all participants were switched to ligelizumab 120 mg s.c. pre-filled syringe (PFS) Q4W in an open-label manner and they were offered an opportunity to self-administer ligelizumab outside the clinic. The second half of the treatment period (TRT2) was 52 weeks (from Week 52 to Week 104). Participants with UAS7>6 and <16 or with UAS7 ≥ 16 for whom the benefit-risk was deemed as positive by the investigator at Week 52 of TRT1 were transitioned to the TRT2 (ligelizumab 120 mg s.c. Q4W PFS) unless a decision to stop treatment was made based on a risk-benefit assessment. They were not allowed to discontinue H1- AH background medication. Participants with UAS7 ≤ 6 at Week 52 of TRT1 entered the second (investigational treatment-free) observation period (OBS2) for up to 52 weeks and remained on the same H1-AH background medication they were taking in the preceding studies. Participants with UAS7 ≤ 6 at Week 52 of TRT1 who entered the second observation period (OBS2) and relapsed (UAS7 ≥ 16) were transitioned to the TRT2 and were also offered the opportunity to discontinue their H1-AH background medication (i.e. ligelizumab 120 mg s.c. q4w PFS monotherapy) after 12 weeks in TRT2. Participants who entered the OBS2 and did not relapse (UAS7<16) exited the study at the end of the OBS2 period. Finally, participants who were in TRT2 entered the post-treatment follow-up period after treatment discontinuation, with duration of 12 weeks (for participants who did not complete a continuous 104-week treatment) or 52 weeks (for participants who completed the full 104-week treatment period without interruption). Participants who decided to remain on H1-AH background medication continued to use H1-AH background medication. Participants who decided to go off H1- AH background medication continued to remain off.

Official Title
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A Multi-center, Double-blinded and Open-label Extension Study to Evaluate the Efficacy and Safety of Ligelizumab as Retreatment, Self-administered Therapy and Monotherapy in Chronic Spontaneous Urticaria Patients Who Completed Studies CQGE031C2302, CQGE031C2303, CQGE031C2202 or CQGE031C1301

Conditions
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Chronic Spontaneous Urticaria

Intervention / Treatment
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* Drug: Ligelizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Written informed consent Subjects who successfully completed all of the treatment period and the follow-up period in any of the following studies: CQGE031C2302 (NCT03580369), CQGE031C2303 (NCT03580356), CQGE031C2202 (NCT03437278) or CQGE031C1301 (NCT03907878) Male and female, adult and adolescent subjects ≥12 years of age Willing and able to complete a daily symptom eDiary for the duration of the study and adhere to the study visit schedule Key Exclusion Criteria: Use of investigational drugs, other than those in use in the preceding studies, at the time of enrollment Use of omalizumab within 16 weeks of Screening History of hypersensitivity to the study drug ligelizumab or its components, or to drugs of similar chemical classes New onset or signs and symptoms of any form of chronic urticarias other than CSU during the preceding studies CQGE031C2302 (NCT03580369), CQGE031C2303 (NCT03580356) or CQGE031C2202 (NCT03437278). Diseases with possible symptoms of urticaria or angioedema Subjects with evidence of helminthic parasitic infection Documented history of anaphylaxis Pregnant or nursing (lactating) women

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ligelizumab 72 mg LIVI -ligelizumab 120 mg PFS<br>Participants received 72 mg of ligelizumab liquid in vial (LIVI) subcutaneously every 4 weeks for the first 12 weeks. Thereafter, participants received 120 mg of ligelizumab pre-filled syringe (PFS) subcutaneously every 4 weeks for up to 92 additional weeks (continuous or interrupted if the participant entered the observation period 2). | Drug: Ligelizumab<br>* For the first 12 weeks of treatment: i) participants transitioning from CQGE031C2302 (NCT03580369) and CQGE031C2303 (NCT03580356) previously treated with ligelizumab 72 mg LIVI s.c. Q4W were treated with the same dose regimen in a double-blind manner; ii) all other participants transitioning from CQGE031C2302 (NCT03580369) and CQGE031C2303 (NCT03580356) were treated with ligelizumab 120 mg LIVI s.c. Q4W in a double-blind manner; iii) participants transitioning from CQGE031C1301 (NCT03907878) and CQGE031C2202 (NCT03437278) were treated with ligelizumab 120 mg LIVI s.c. Q4W in an open-label manner. Thereafter, all participants were switched to ligelizumab 120 mg s.c. PFS Q4W in an open-label manner and they were offered an opportunity to self-administer ligelizumab. The longest possible treatment was 104 weeks, however this treatment might not be continuous and might span over a period of 156 weeks due to the possibility of entering the intervening observation period.<br>* Other names: QGE031;|
| Experimental: Ligelizumab 120 mg LIVI -ligelizumab 120 mg PFS<br>Participants received 120 mg of ligelizumab liquid in vial (LIVI) subcutaneously every 4 weeks for the first 12 weeks. Thereafter, participants received 120 mg of ligelizumab pre-filled syringe (PFS) subcutaneously every 4 weeks for up to 92 additional weeks (continuous or interrupted if the participant entered the observation period 2). | Drug: Ligelizumab<br>* For the first 12 weeks of treatment: i) participants transitioning from CQGE031C2302 (NCT03580369) and CQGE031C2303 (NCT03580356) previously treated with ligelizumab 72 mg LIVI s.c. Q4W were treated with the same dose regimen in a double-blind manner; ii) all other participants transitioning from CQGE031C2302 (NCT03580369) and CQGE031C2303 (NCT03580356) were treated with ligelizumab 120 mg LIVI s.c. Q4W in a double-blind manner; iii) participants transitioning from CQGE031C1301 (NCT03907878) and CQGE031C2202 (NCT03437278) were treated with ligelizumab 120 mg LIVI s.c. Q4W in an open-label manner. Thereafter, all participants were switched to ligelizumab 120 mg s.c. PFS Q4W in an open-label manner and they were offered an opportunity to self-administer ligelizumab. The longest possible treatment was 104 weeks, however this treatment might not be continuous and might span over a period of 156 weeks due to the possibility of entering the intervening observation period.<br>* Other names: QGE031;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects From Core Studies (CQGE031C2302 and CQGE031C2303), Receiving the Same Dose Regimen as in the Core Studies, With Well-controlled Disease (UAS7 ≤ 6) at Week 12 | The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. UAS7 scores ranged from 0 to 42. A higher UAS7 indicated greater urticaria disease activity. A minimum of 4 out of 7 daily scores were needed to calculate the UAS7 values. Otherwise, the weekly score was missing for that week. The percentage of subjects transitioning from CQGE031C2302 and CQGE031C2303 and receiving the same dose regimen as in the core studies with UAS7≤ 6 at Week 12 was estimated using multiple imputation method. The 95% confidence interval was derived based on the Wilson score method with continuity correction. | Week 12 of the extension study | 
| Percentage of Subjects From Core Studies (CQGE031C2302 and CQGE031C2303), Receiving the Same Dose Regimen as in Core Studies and Who Achieved UAS7≤ 6 at Week 12 in Core Studies, With Well-controlled Disease (UAS7 ≤ 6) at Week 12 of the Extension Study | The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals and the intensity of the pruritus over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. UAS7 scores ranged from 0 to 42. A higher UAS7 indicated greater urticaria disease activity. A minimum of 4 out of 7 daily scores were needed to calculate the UAS7 values. Otherwise, the UAS7 was missing for that week. Missing data was considered as non-responder. The percentage of subjects transitioning from core studies (CQGE031C2302 and CQGE031C2303) and receiving the same dose regimen as in the core studies who achieved UAS7 ≤ 6 at week 12 in the core studies with UAS7≤ 6 at Week 12 of the extension study was estimated based on observed data. | Week 12 of the extension study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects From Core Studies (CQGE031C2302 and CQGE031C2303), Receiving the Same Dose Regimen as in the Core Studies, With Completely Controlled Disease (UAS7 =0) at Week 12 | The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. UAS7 scores ranged from 0 to 42. A higher UAS7 indicated greater urticaria disease activity. A minimum of 4 out of 7 daily scores were needed to calculate the UAS7 values. Otherwise, the weekly score was missing for that week. The percentage of subjects transitioning from core studies (CQGE031C2302 and CQGE031C2303) and receiving the same dose regimen as in the core studies with UAS7 = 0 at Week 12 was estimated using multiple imputation method. | Week 12 of the extension study | 
| Change From Extension Study Baseline in the UAS7 at Week 12 in All Subjects From Core Studies (CQGE031C2302 and CQGE031C2303) Receiving the Same Dose Regimen as in the Core Studies | The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. UAS7 scores ranged from 0 to 42. A higher UAS7 indicated greater urticaria disease activity. A negative change score from extension study baseline indicates improvement. A minimum of 4 out of 7 daily scores were needed to calculate the UAS7 values. Otherwise, the weekly score was missing for that week. The absolute change from extension study baseline in the UAS7 at Week 12 was estimated using multiple imputation method. | Extension study baseline (Week 0), Week 12 of the extension study | 
| Change From Extension Study Baseline in the ISS7 at Week 12 in All Subjects From Core Studies (CQGE031C2302 and CQGE031C2303) Receiving the Same Dose Regimen as in the Core Studies | The Itch Severity Score (ISS) was recorded by the subject twice daily in their eDiary, on a scale of 0 (none) to 3 (intense/severe). A weekly score (ISS7) was derived by adding up the average daily scores of the 7 preceding days. The ISS7 ranged from 0 to 21. A higher ISS7 indicated more severe itching. A negative change score from baseline indicates improvement. A minimum of 4 out of 7 daily scores were needed to calculate the ISS7 values. Otherwise, the weekly score was missing for that week. The absolute change from extension study baseline in the ISS7 at Week 12 in all subjects from core studies (CQGE031C2302 and CQGE031C2303) receiving the same dose regimen as in the core studies was estimated using multiple imputation method. | Extension study baseline (Week 0), Week 12 of the extension study | 
| Change From Extension Study Baseline in the HSS7 at Week 12 in All Subjects From Core Studies (CQGE031C2302 and CQGE031C2303) Receiving the Same Dose Regimen as in the Core Studies | The Hive Severity Score (HSS) was recorded by the subject twice daily in their eDiary, on a scale of 0 (none) to 3 (> 12 hives/12 hours). A weekly score (HSS7) was derived by adding up the average daily scores of the 7 preceding days. The HSS7 ranged from 0 to 21 A higher HSS7 indicated a greater number of hives. A negative change score from baseline indicates improvement. A minimum of 4 out of 7 daily scores were needed to calculate the HSS7 values. Otherwise, the weekly score was missing for that week. The absolute change from extension study baseline in the HSS7 at Week 12 in all subjects from core studies (CQGE031C2302 and CQGE031C2303) receiving the same dose regimen as in the core studies was estimated using multiple imputation method. | Extension study baseline (Week 0), Week 12 of the extension study | 
| Cumulative Number of Angioedema-free Weeks (AAS7=0) up to Week 12 in All Subjects From Core Studies (CQGE031C2302 and CQGE031C2303) Receiving the Same Dose Regimen as in the Core Studies | The Weekly angioedema activity score (AAS) is a validated tool to assess occurrence of episodes of angioedema. If the subject reported the occurrence of angioedema (opening question) with no, AAS score for this day was 0. If yes was the answer to the opening question, the subject continued to answer questions about the duration, severity and impact on daily functioning and appearance of the angioedema. A score between 0 and 3 was assigned to every answer field. The AAS7 was the weekly sum of the daily AAS. AAS7 scores ranged from 0-105. Higher score indicated more severe disease. AAS7 in all subjects from core studies (CQGE031C2302 and CQGE031C2303) receiving the same dose regimen as in the core studies was estimated using multiple imputation method. The imputed AAS7 = 0 was used for the cumulative number of weeks that subjects achieved AAS7 = 0 response calculation | From extension study baseline (Week 0) up to Week 12 of the extension study | 
| Percentage of Subjects From Core Studies (CQGE031C2302 and CQGE031C2303), Receiving the Same Dose Regimen as in the Core Studies, With DLQI = 0-1 at Week 12 | The Dermatology Life Quality Index (DLQI) is a 10-item dermatology-specific quality of life (QoL) measure. Subjects rated their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives thinking about the previous 7 days. An overall score was calculated and ranged from 0 to 30. Higher scores indicated worse disease-related QoL. A DLQI score of 0 or 1 indicated that there was no impact of a skin disease on the patient's life. The percentage of subjects from core studies (CQGE031C2302 and CQGE031C2303) receiving the same dose regimen as in the core studies with DLQI = 0-1 at Week 12 was estimated using multiple imputation method. | Week 12 of the extension study | 
| Percentage of Subjects With Well-controlled Disease (UAS7 ≤ 6) 12 Weeks After Starting Self-administration | The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. UAS7 scores ranged from 0 to 42. A higher UAS7 indicated greater urticaria disease activity. A minimum of 4 out of 7 daily scores were needed to calculate the UAS7 values. Otherwise, the weekly score was missing for that week. Missing data was considered as non-responder in the analysis. The percentage of subjects with UAS7≤ 6 at Week 24 (i.e., 12 weeks after starting self-administration) was estimated based on observed data. | Week 24 of the extension study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-IgE, chronic spontaneous urticaria, hives severity score, itch severity score, urticaria activity score, CSU