Study to Investigate the Efficacy and Safety of QGE031 in Adolescent Patients With Chronic Spontaneous Urticaria (CSU)

This was a Phase IIb dose-finding, randomized, double-blind, parallel-group, placebo-controlled, multicenter study in adolescent patients. The study consisted of 3 distinct study periods: Screening, Treatment and Follow-up period.

After the screening period (up to 4 weeks), at Day 1 participants were randomized into one of the three treatment arms in 1:2:1 fashion to ligelizumab high dose (120 mg every four weeks (q4w)) versus ligelizumab low dose (24 mg q4w) versus placebo. During the 24 weeks of treatment period, doses were administered on Day 1 then on weeks 4, 8, 12, 16, and 20 weeks after randomization. Participants randomized to placebo received placebo on Day 1, Weeks 4 and 8; thereafter they received 120 mg ligelizumab (high dose) on Weeks 12, 16 and 20 such that by the end of the study, the same number of participants received ligelizumab high dose as low dose. The treatment period was followed by a treatment-free follow-up period of 16 weeks to a maximum of Week 40.

• Ligelizumab (Drug), also known as QGE031: Ligelizumab comes in 120 mg per 1 ml liquid vials. Participants received one injection every 4 weeks at a dose of 120 mg or 24 mg, high and low doses respectively.
• Placebo (Drug): Placebo 0 mg per 1 ml liquid injection once every 4 weeks.

Primary outcomes

• Change From Baseline of Weekly Urticaria Activity Score (UAS7) at Week 24 [Baseline, week 24]: UAS7 is a self-reported scoring system to evaluate urticaria signs and symptoms. UAS7 is the sum of daily urticaria activity scores (UAS) over a seven-day period. The possible range of UAS7 score is 0 to 42 (0 to 6 for daily UAS x 7 days). A higher urticaria activity score indicates more severe symptoms. A negative change score from baseline indicates improvement. Baseline was calculated using data from the 7 days prior to the first treatment date. To handle the missing data, if a participant had at least 4 non-missing daily scores within the 7 days prior to a study visit, the weekly score was calculated as the sum of the available scores in that week, divided by the number of days with daily scores available, multiplied by 7. However, if there were less than 4 non-missing daily scores within the prior 7 days, then the weekly score was missing for the week.

Secondary outcomes

• Change From Baseline of Weekly Urticaria Activity Score (UAS7) at Weeks 12 and 40 [Baseline, weeks 12 and 40]: UAS7 is a self-reported scoring system to evaluate urticaria signs and symptoms. UAS7 is the sum of daily urticaria activity scores (UAS) over a seven-day period. The possible range of UAS7 score is 0 to 42 (0 to 6 for daily UAS x 7 days). A higher urticaria activity score indicates more severe symptoms. A negative change score from baseline indicates improvement. Baseline was calculated using data from the 7 days prior to the first treatment date. To handle the missing data, if a participant had at least 4 non-missing daily scores within the 7 days prior to a study visit, the weekly score was calculated as the sum of the available scores in that week, divided by the number of days with daily scores available, multiplied by 7. However, if there were less than 4 non-missing daily scores within the prior 7 days, then the weekly score was missing for the week.
• Percentage of Participants With Complete Response in Weekly Urticaria Activity Score (UAS7) [Weeks 12, 24 and 40]: UAS7 is a self-reported scoring system to evaluate urticaria signs and symptoms. UAS7 is the sum of daily urticaria activity scores (UAS) over a seven-day period. The possible range of UAS7 score is 0 to 42 (0 to 6 for daily UAS x 7 days). A higher urticaria activity score indicates more severe symptoms. A complete UAS7 response is defined as UAS7=0, no wheals neither pruritus. Participants with post-baseline missing data were considered as non-responders.
• Change From Baseline of Weekly Itch Severity Score (ISS7) [Baseline, weeks 12, 24 and 40]: ISS7 is the sum of daily Itch Severity Score (ISS) over a seven-day period. The possible range of ISS7 score is 0-21 (0-3 for daily ISS x 7 days), where 0 is defined as complete ISS7 response (no itching) and 21 is the worst score. A negative change score from baseline indicates improvement. Baseline was calculated using data from the 7 days prior to the first treatment date. To handle the missing data, if a participant had at least 4 non-missing daily scores within the 7 days prior to a study visit, the weekly score was calculated as the sum of the available scores in that week, divided by the number of days with daily scores available, multiplied by 7. However, if there were less than 4 non-missing daily scores within the prior 7 days, then the weekly score was missing for the week.
• Percentage of Participants With Complete Response in Weekly Itch Severity Score (ISS7) [Weeks 12, 24 and 40]: ISS7 is the sum of daily Itch Severity Score (ISS) over a seven-day period. The possible range of ISS7 score is 0-21 (0-3 for daily ISS x 7 days), where 0 is defined as complete ISS7 response (no itching) and 21 is the worst score. Participants with post-baseline missing data were considered as non-responders.
• Change From Baseline of Weekly Hives Severity Score (HSS7) [Baseline, weeks 12, 24 and 40]: HSS7 is the sum of daily Hives Severity Score (HSS) over a seven-day period. The possible range of HSS7 score is 0-21 (0-3 for daily HSS x 7 days), where 0 is defined as complete HSS7 response (no wheals) and 21 is the worst score. A negative change score from baseline indicates improvement. Baseline was calculated using data from the 7 days prior to the first treatment date. To handle the missing data, if a participant had at least 4 non-missing daily scores within the 7 days prior to a study visit, the weekly score was calculated as the sum of the available scores in that week, divided by the number of days with daily scores available, multiplied by 7. However, if there were less than 4 non-missing daily scores within the prior 7 days, then the weekly score was missing for the week.
• Percentage of Participants With Complete Response in Weekly Hives Severity Score (HSS7) [Weeks 12, 24 and 40]: HSS7 is the sum of daily Hives Severity Score (HSS) over a seven-day period. The possible range of HSS7 score is 0-21 (0-3 for daily HSS x 7 days), where 0 is defined as complete HSS7 response (no wheals) and 21 is the worst score. Participants with post-baseline missing data were considered as non-responders.
• Change From Baseline of the Children Dermatology Life Quality Index (CDLQI) [Baseline, weeks 12, 24 and 40]: The children dermatology life quality index questionnaire is a 10-item dermatology- specific health-related quality of life measure designed for use in children. Participants rated their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives. The CDLQI total score is a sum of all 10 item responses, each individual response ranging from 0 (not at all) to 3 (very much). Total score ranges from 0 to 30 with higher scores indicating greater health-related quality of life impairment. A negative change score from baseline indicates improvement. Baseline was defined as the last non-missing value prior to or on the first treatment date. To handle the missing data, if a participant had only one item missing score per visit, then it was imputed to 0 and total score was calculated accordingly. If there were 2 or more item missing scores per visit, then the total score for the visit was considered as missing.
• Change From Baseline in Total Human Immunoglobulin E (IgE) [Baseline, weeks 12, 24 and 40]: Change from baseline in IgE (free IgE plus IgE bound to ligelizumab) at weeks 12, 24 and 40 as a pharmacodynamic measurement.
• Apparent Clearance (CL/F) of Ligelizumab Estimated With a PopPK Model [Weeks 0 (baseline), 4, 8, 12, 16, 20 (all pre-dose) and weeks 24, 32 and 40]: Model-based estimate of apparent clearance (CL/F) was derived using compartmental pharmacokinetic population (PopPK) modelling using non-linear mixed effects model for ligelizumab. Apparent clearance population estimate was derived through fitting individual drug administration history and collected ligelizumab concentrations at the specified data points (listed in Time Frame).
• Apparent Volume of Distribution of Ligelizumab Estimated With a PopPK Model [Weeks 0 (baseline), 4, 8, 12, 16, 20 (all pre-dose) and weeks 24, 32 and 40]: Model-based estimate of apparent volume of distribution was derived using compartmental pharmacokinetic population (PopPK) modelling using non-linear mixed effects model for ligelizumab. Apparent volume of distribution population estimate was derived through fitting individual drug administration history and collected ligelizumab concentrations at the specified data points (listed in Time Frame).
• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From the start of treatment to 20 weeks after end of treatment, assessed up to maximum duration of 40 weeks]: Number of participants with AEs and SAEs, including significant changes from baseline in vital signs (blood pressure, pulse rate), electrocardiograms and laboratory values qualifying and reported as AEs. The number of participants in each category is reported in the table.

Sex: All, ages: 12 Years to 17 Years

Inclusion Criteria:

* Parent or legal guardian's written informed consent and child's assent, if appropriate, must be obtained before any study related activity or assessment is performed. Of note, if the subject reaches age of consent (age as per local law) during the study, they will also need to sign the corresponding study ICF (Informed Consent Form) at the next study visit.
* Male and female adolescent patients aged ≥ 12 to <18 years at the time of screening.
* Diagnosis of CSU refractory to approved doses of H1-antihistamines at the time of randomization, as defined by all of the following:

  * The presence of itch and hives for at least 6 consecutive weeks at any time prior to enrollment despite current use of non-sedating H1-antihistamines during this time period
  * UAS7 score (range 0 - 42) ≥ 16 and HSS7 (range 0 - 21) ≥ 8 during 7 days prior to randomization (Day 1)
  * In-clinic UAS ≥ 4 on at least one of the screening visit days or Day 1 or a medical record of the presence of hives (confirmed and documented by a physician); patients must have been on H1-antihistamines for treatment of CSU at the time of in-clinic UAS at screening visit and/or time of the medical record of hives (for at least 3 days prior to the in-clinic UAS or medical record) • Patients must have been on H1-antihistamines for treatment of CSU for at least the 3 consecutive days immediately prior to the first screening visit and must have documented current use on the day of the initial screening visit
  * CSU diagnosis for ≥ 6 months
* Willing and able to complete a daily symptom e-Diary for the duration of the study and adhere to the study visit schedules.
* Demonstration of compliance with the e-Diary: patients should not have had any missing e-Diary entries in the 7 days prior to randomization. Re-screening may be considered.

Exclusion Criteria:

* Clearly defined underlying etiology for chronic urticarias other than CSU. This includes the following:

  * Inducible urticaria: urticaria factitia, cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, cholinergic-, or contact-urticaria
  * Diseases with possible symptoms of urticaria or angioedema such as urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa), and hereditary or acquired angioedema (e.g., due to C1 inhibitor deficiency)
* Any other skin disease associated with chronic itching that might confound the study evaluations and results (e.g. atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis etc.)
* Previous exposure to omalizumab
* History of anaphylaxis

Participant flow

Outcome results

• Change From Baseline of Weekly Urticaria Activity Score (UAS7) at Week 24 (Primary), Mean, Score on a scale: Ligelizumab 24 mg -20.36 +/- 12.963; Ligelizumab 120 mg -22.50 +/- 13.503; Placebo + Ligelizumab 120 mg -21.26 +/- 14.480
• Change From Baseline of Weekly Urticaria Activity Score (UAS7) at Weeks 12 and 40 (Secondary), Mean, Score on a scale: Ligelizumab 24 mg -15.70 +/- 10.867; Ligelizumab 120 mg -18.38 +/- 12.268; Placebo + Ligelizumab 120 mg -12.96 +/- 13.043
• Percentage of Participants With Complete Response in Weekly Urticaria Activity Score (UAS7) (Secondary), Count of participants, Participants: Ligelizumab 24 mg 4; Ligelizumab 120 mg 5; Placebo + Ligelizumab 120 mg 2
• Change From Baseline of Weekly Itch Severity Score (ISS7) (Secondary), Mean, Score on a scale: Ligelizumab 24 mg -7.66 +/- 5.824; Ligelizumab 120 mg -7.81 +/- 6.047; Placebo + Ligelizumab 120 mg -6.34 +/- 6.936
• Percentage of Participants With Complete Response in Weekly Itch Severity Score (ISS7) (Secondary), Count of participants, Participants: Ligelizumab 24 mg 4; Ligelizumab 120 mg 5; Placebo + Ligelizumab 120 mg 2
• Change From Baseline of Weekly Hives Severity Score (HSS7) (Secondary), Mean, Score on a scale: Ligelizumab 24 mg -8.03 +/- 6.307; Ligelizumab 120 mg -10.58 +/- 7.225; Placebo + Ligelizumab 120 mg -6.62 +/- 6.385
• Percentage of Participants With Complete Response in Weekly Hives Severity Score (HSS7) (Secondary), Count of participants, Participants: Ligelizumab 24 mg 6; Ligelizumab 120 mg 6; Placebo + Ligelizumab 120 mg 2
• Change From Baseline of the Children Dermatology Life Quality Index (CDLQI) (Secondary), Mean, Score on a scale: Ligelizumab 24 mg -10.1 +/- 4.88; Ligelizumab 120 mg -6.6 +/- 8.05; Placebo + Ligelizumab 120 mg -5.0 +/- 6.23
• Change From Baseline in Total Human Immunoglobulin E (IgE) (Secondary), Mean, International units / millilitre: Ligelizumab 24 mg 186 +/- 160; Ligelizumab 120 mg 245 +/- 291; Placebo + Ligelizumab 120 mg -43.1 +/- 56.2
• Apparent Clearance (CL/F) of Ligelizumab Estimated With a PopPK Model (Secondary), Median, Liters / day: All Participants With PK Data 0.66 (0.44 to 1.03)
• Apparent Volume of Distribution of Ligelizumab Estimated With a PopPK Model (Secondary), Median, Liters: All Participants With PK Data 14.5 (11.02 to 16.65)
• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) (Secondary), Count of participants, Participants: Ligelizumab 24 mg 18; Ligelizumab 120 mg 11; Placebo + Ligelizumab 120 mg 9

Adverse events

Time frame: Adverse events were reported from the start treatment to 20 weeks after end of treatment, assessed up to maximum duration of 40 weeks.

Serious adverse events by term

Other adverse events by term

• Results publication: Staubach P, Alvaro-Lozano M, Sekerel BE, Maurer M, Ben-Shoshan M, Porter M, Hua E, Ji Y, Burciu A, Savelieva M, Severin T, Drollmann A, Bienczak A. Ligelizumab in adolescents with chronic spontaneous urticaria: Results of a dedicated phase 2b randomized clinical trial supported with pharmacometric analysis. Pediatr Allergy Immunol. 2023 Jul;34(7):e13982. doi: 10.1111/pai.13982. PMID 37492920

• Study Protocol (PDF, 2018-01-18)
• Statistical Analysis Plan (PDF, 2021-03-11)

NIH grants: 2017