To Compare Efficacy and Safety of CT-P39 and EU-approved Xolair in Patients With Chronic Spontaneous Urticaria

Phase 3

Completed

Conditions: Chronic Spontaneous Urticaria

Interventions: Biological: CT-P39
Biological: EU-approved Xolair

Registration Number: NCT04426890

Lead Sponsor: Celltrion

Brief Summary: A Double-blind, Randomized, Active-controlled, Parallel Group, Phase 3 Study to Compare Efficacy and Safety of CT-P39 and Xolair in Patients with Chronic Spontaneous Urticaria Who Remain Symptomatic despite H1 antihistamine Treatment

Detailed Description: CT-P39, containing the active ingredient omalizumab, is a recombinant humanized monoclonal antibody that is being developed and manufactured as a proposed biosimilar to Xolair (omalizumab) by the Sponsor. CT-P39 is identical to Xolair with respect to concentration and presentation. The 150 mg of drug product (CT-P39) will have the same pharmaceutical form and strength as 150 mg Xolair (in a prefilled syringe \[PFS\] for subcutaneous injection) and is intended to have a similar quality profile compared with Xolair.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 634

Inclusion Criteria

Diagnosed with CSU
Diagnosed as CSU refractory to H1-antihistamine

Exclusion Criteria

Chronic urticaria with clearly defined underlying etiology
Clinically significant allergic reaction and/or hypersensitivity to any component of omalizumab
History of anaphylactic shock
History of and/or concomitant immune complex disease (including Type III hypersensitivity)
Parasitic diseases or colonization on stool evaluation for ova and parasites
Unable to receive background therapy with protocol-defined antihistamines or contraindicated to epinephrine

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1	CT-P39	Planned to receive CT-P39 300 mg every 4 weeks in Treatment Period 1 (TP1) and maintain CT-P39 300 mg in TP2
Arm 2	EU-approved Xolair	Planned to receive Xolair 300 mg every 4 weeks in TP1 and be re-randomized at Week 12 to Arm 2-1 or Arm 2-2
Arm 2-1	CT-P39	Planned to receive Xolair 300 mg every 4 weeks in TP1 and be re-randomized to switch to CT-P39 300 mg in TP2
Arm 2-2	EU-approved Xolair	Planned to receive Xolair 300 mg every 4 weeks in TP1 and be re-randomized to maintain Xolair 300 mg in TP2
Arm 2-1	EU-approved Xolair	Planned to receive Xolair 300 mg every 4 weeks in TP1 and be re-randomized to switch to CT-P39 300 mg in TP2
Arm 3	CT-P39	Planned to receive CT-P39 150 mg every 4 weeks in Treatment Period 1 (TP1) and increase to CT-P39 300 mg in TP2
Arm 4	EU-approved Xolair	Planned to receive Xolair 150 mg every 4 weeks in Treatment Period 1 (TP1) and increase to Xolair 300 mg in TP2

Primary Outcome Measures

Name	Time	Method
Therapeutic Equivalence Based on Change From Baseline in ISS7 at Week 12 in 300 mg Groups	Week 12	The primary efficacy evaluation was comparison of mean change from baseline in ISS7 of 300 mg of CT-P39 (Arm 1) and 300 mg of Xolair (Arm 2) at Week 12, calculated as ISS7 at Week 12 minus the baseline ISS7. The ISS was recorded twice daily (morning and evening) in the patient eDiary, on scale of 0 (none) to 3 (severe) points. The daily ISS is the average of the morning and evening scores and the ISS7 is the sum of the daily ISS over 7 days. The ISS7 can range from 0 to 21. The higher scores mean a worse outcome. The analysis was conducted by analysis of covariance (ANCOVA). The ANCOVA model included the treatment group as a fixed effect and baseline ISS7, body weight on Day 1 and country as covariates.
Relative Potency of CT-P39 Compared With Xolair Based on Change From Baseline in ISS7 at Week 12	Week 12	The ISS was recorded twice daily (morning and evening) in the patient eDiary, on scale of 0 (none) to 3 (severe) points. The daily ISS is the average of the morning and evening scores and the ISS7 is the sum of the daily ISS over 7 days. The ISS7 can range from 0 to 21. The higher scores mean a worse outcome. The relative potency was not calculated due to the assumption of parallel-line assay not being met. A parallel-line assay assumes that dose-efficacy response relationships are linear and parallel on log-dose scale which requires the equal slope in the regression model used to estimate relative potency. However, the slopes of the two treatment groups were estimated to be different, indicating a violation of the parallelism assumption. As a result, the relative potency was not computed.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Weekly Itch Severity Score (ISS7) at Week 12	Week 12	The change from baseline in ISS7 at Week 12 was calculated as ISS7 at Week 12 minus the baseline ISS7. The ISS was recorded twice daily (morning and evening) in the patient eDiary, on scale of 0 (none) to 3 (severe) points. The daily ISS is the average of the morning and evening scores and the ISS7 is the sum of the daily ISS over 7 days. The ISS7 can range from 0 to 21. The higher scores mean a worse outcome. The relative potency based on the CFB of ISS7 at Week 12 was not calculated due to assumption of parallel-line assay not being met.
Time to Minimally Important Difference (MID) in ISS7 by Week 12	Up to Week 12	Time to MID response was the time (in weeks) from Day 1 to the study week when reduction of 5 points or more from baseline for ISS7 was first achieved up to Week 12. If a patient failed to achieve an MID response up to Week 12 or terminated the study prior to Week 12 without achieving MID response, the patient was censored at the date (in weeks) of the last non-missing ISS7 evaluation. Time to MID was estimated by Kaplan-Meier method. The lower result means a better outcome.
Change From Baseline in Weekly Itch Severity Score (ISS7) at Week 24	Week 24	The change from baseline in ISS7 at Week 24 was calculated as ISS7 at Week 24 minus the baseline ISS7. The ISS was recorded twice daily (morning and evening) in the patient eDiary, on scale of 0 (none) to 3 (severe) points. The daily ISS is the average of the morning and evening scores and the ISS7 is the sum of the daily ISS over 7 days. The ISS7 can range from 0 to 21. The higher scores mean a worse outcome.
Percentage of Minimally Important Difference (MID) Responders in ISS7 at Week 12	Week 12	Number of patients who achieved MID response at Week 12 were presented. MID response is a change from baseline in ISS7 of ≤ -5. If a patient had missing weekly scores for the given week the patient was classified as a non-responder. The higher percentage means a better outcome.
Change From Baseline in Weekly Hives Severity Score (HSS7) at Week 12	Week 12	The change from baseline in HSS7 at Week 12 was calculated as HSS7 at Week 12 minus the baseline HSS7. The HSS was counted twice daily (morning and evening) in the patient eDiary, on a scale of 0 (none) to 3 (intense) points. The daily HSS is the average of the morning and evening scores, and the HSS7 is the sum of the daily HSS over 7 days. HSS7 can range from 0 to 21. The higher scores mean a worse outcome.
Change From Baseline in Weekly Hives Severity Score (HSS7) at Week 24	Week 24	The change from baseline in HSS7 at Week 24 was calculated as HSS7 at Week 24 minus the baseline HSS7. The HSS was counted twice daily (morning and evening) in the patient eDiary, on a scale of 0 (none) to 3 (intense) points. The daily HSS is the average of the morning and evening scores, and the HSS7 is the sum of the daily HSS over 7 days. HSS7 can range from 0 to 21. The higher scores mean a worse outcome.
Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 12	Week 12	The change from baseline in UAS7 at Week 12 was calculated as UAS7 at Week 12 minus the baseline UAS7. The UAS was calculated as the sum of the ISS and the HSS by diary-based documentation. The sum of the scores represented disease severity on a scale from 0 (minimum) to 6 (maximum). The daily UAS is the average of the morning and evening scores and the UAS7 is the sum of the daily UAS over 7 days. UAS7 can range from 0 to 42. The higher scores mean a worse outcome.
Change From Baseline in Number of Tablets/Week of Rescue Therapy at Week 24	Week 24	The change from baseline in the number of tablets/week of rescue therapy used at Week 24 is presented. The number of tablets for each week of rescue therapy will be defined as the sum of daily use of rescue therapy over the study days which make up a given study week. The higher value means a worse outcome. If a subject switched rescue therapy medication and started a different medication or the prescribed dose of the rescue therapy medication changed during the study, the subject was excluded from the summary.
Change From Baseline in the Overall Dermatology Life Quality Index (DLQI) Score at Week 12	Week 12	The change from baseline in mean overall DLQI score at Week 12 is presented. The DLQI is a 10-item dermatology-specific health-related questionnaire across 6 domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Patients rated their dermatology symptoms as well as the impact of their skin condition on various aspect of their lives. Each question is scored from 0 to 3. Overall DLQI ranges on a scale of 0 to 30. The higher result means a worse outcome.
Change From Baseline in the Overall Dermatology Life Quality Index (DLQI) Score at Week 24	Week 24	The change from baseline in mean overall DLQI score at Week 24 is presented. The DLQI is a 10-item dermatology-specific health-related questionnaire across 6 domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Patients rated their dermatology symptoms as well as the impact of their skin condition on various aspect of their lives. Each question is scored from 0 to 3. Overall DLQI ranges on a scale of 0 to 30. The higher result means a worse outcome.
Change From Baseline in the Overall Chronic Urticaria Quality of Life Questionnaire Score (CU-Q2oL) Score at Week 12	Week 12	The change from baseline in mean overall CU-Q2oL score at Week 12 is presented. The CU-Q2oL is a 23-item CSU specific health-related QoL questionnaire across 6 domains: pruritus, swelling, impact on life activities, sleep problems, limits, and looks. Patients rated their CSU symptoms and the impact of their CSU on various aspects of their lives. Each question was scored from 1 (not at all) to 5 (extremely), and overall raw score, on a scale of 23 to 115, was calculated by summing the individual raw domain scores. The higher result means a worse outcome. Overall raw scores of CU-Q2oL were converted to 0 to 100 point scores according to the following formula:\[(sum of items - minimum) / (maximum - minimum)\] × 100, where minimum=23 (1 score for all 23 items), maximum=115 (5 score for all 23 items).
Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 24	Week 24	The change from baseline in UAS7 at Week 24 was calculated as UAS7 at Week 24 minus the baseline UAS7. The UAS was calculated as the sum of the ISS and the HSS by diary-based documentation. The sum of the scores represented disease severity on a scale from 0 (minimum) to 6 (maximum). The daily UAS is the average of the morning and evening scores and the UAS7 is the sum of the daily UAS over 7 days. UAS7 can range from 0 to 42. The higher scores mean a worse outcome.
Change From Baseline in the Overall Chronic Urticaria Quality of Life Questionnaire Score (CU-Q2oL) Score at Week 24	Week 24	The change from baseline in mean overall CU-Q2oL score at Week 24 is presented. The CU-Q2oL is a 23-item CSU specific health-related QoL questionnaire across 6 domains: pruritus, swelling, impact on life activities, sleep problems, limits, and looks. Patients rated their CSU symptoms and the impact of their CSU on various aspects of their lives. Each question was scored from 1 (not at all) to 5 (extremely), and overall raw score, on a scale of 23 to 115, was calculated by summing the individual raw domain scores. The higher result means a worse outcome. Overall raw scores of CU-Q2oL were converted to 0 to 100 point scores according to the following formula: \[(sum of items - minimum) / (maximum - minimum)\] × 100, where minimum=23 (1 score for all 23 items), maximum=115 (5 score for all 23 items)
Trough Serum Concentration (Ctrough) of Omalizumab at Week 12	Week 12	All concentration below lower limit of quantification (BLQ) values were treated as zero (0) for PK parameter summary. Below lower limit of quantification (BLQ) is treated as zero (0).
Trough Serum Concentration (Ctrough) of Omalizumab at Week 24	Week 24	All concentration below lower limit of quantification (BLQ) values were treated as zero (0) for PK parameter summary. Below lower limit of quantification (BLQ) is treated as zero (0).
Immunogenicity Result at Week 12	Week 12	Anti-drug Antibody test involved both screening and confirmatory assays to confirm true positive results. Samples that are positive in the screening assay underwent further testing in the confirmatory assay to determine if patients are true positive. Samples that are positive in the ADA confirmatory assay were analyzed further to conduct a NAb assessment.
Immunogenicity Result at Week 24	Week 24	Anti-drug Antibody test involved both screening and confirmatory assays to confirm true positive results. Samples that are positive in the screening assay underwent further testing in the confirmatory assay to determine if patients are true positive. Samples that are positive in the ADA confirmatory assay were analyzed further to conduct a NAb assessment.
Percentage of Patients With UAS7 of ≤ 6 Points and Complete Responders in Weekly Urticaria Activity Score at Week 12	Week 12	Percentage of patients with Weekly Urticaria Activity Score (UAS7) of ≤ 6 points and complete responders (UAS7 = 0) at Week 12 is presented. If a patient had missing weekly scores for the given week the patient was classified as a non-responder. UAS7 can range from 0 to 42. The higher result means a better outcome.
Percentage of Patients With UAS7 of ≤ 6 Points and Complete Responders in Weekly Urticaria Activity Score at Week 24	Week 24	The number of patients with Weekly Urticaria Activity Score (UAS7) of ≤ 6 points and complete responders (UAS7 = 0) at Week 24 is presented. If a patient had missing weekly scores for the given week the patient was classified as a non-responder. UAS7 can range from 0 to 42. The higher result means a better outcome.
Percentage of Angioedema-Free Days From Week 4 to Week 12	Week 4 to 12	The proportion of angioedema-free days from Week 4 to Week 12 is defined as the number of days for which the patient indicated a 'No' response to the angioedema question in the patient eDiary divided by the total number of days with a non-missing diary entry starting on Week 4 visit date and ending the day prior to Week 12 visit date. Patients who had missing responses for \> 40% of the daily diary entries between Week 4 visit date and Week 12 visit date were not included in this analysis. The higher result means a better outcome.
Change From Baseline in Number of Tablets/Week of Rescue Therapy at Week 12	Week 12	The change from baseline in the number of tablets/week of rescue therapy used at Week 12 is presented. The number of tablets for each week of rescue therapy will be defined as the sum of daily use of rescue therapy over the study days which make up a given study week. The higher value means a worse outcome. If a subject switched rescue therapy medication and started a different medication or the prescribed dose of the rescue therapy medication changed during the study, the subject was excluded from the summary.