Chronic Spontaneous Urticaria
Conditions
Keywords
Chronic spontaneous urticaria, BTK Inhibitor, Long term safety, Urticaria activity score
Brief summary
The main objective to assess the long-term safety and tolerability of LOU064 in patients with chronic spontaneous urticaria (CSU) who have participated in study CLOU064A2201 (NCT03926611)
Detailed description
This was an open-label, single-arm, multicenter, long-term safety and tolerability extension study for CSU patients rolling over from study CLOU064A2201 (NCT03926611). Subjects rolling over from CLOU064A2201 with a weekly Urticaria Activity Score (UAS7)\<16 after the follow-up period at Week 16 were further followed up without receiving LOU064 for up to 12 weeks (observational period). If there was a relapse (UAS7≥16 at least once), the 12-week observational period was terminated, and subjects entered the treatment period. Subjects who never relapsed within 12 weeks completed the study after the observational period without treatment. Subjects who rolled over from CLOU064A2201 with a UAS7≥16 at Week 12 or Week 16, as well as those subjects who relapsed during the 12-week observational period, were treated with 100 mg LOU064 twice a day (b.i.d.) open-label for 52 weeks. No background medication with a second-generation H1-antihistamine was permitted up to Week 4 of the treatment period. Subjects who completed the treatment period or who discontinued treatment early were followed-up for a minimum duration of 4 weeks. Subjects who had a UAS7≤6 at Week 52 of the treatment period had their follow-up period extended until relapse (UAS7≥16) for up to a total of 16 weeks.
Interventions
DRUGLOU064
Participants with a UAS7≥16 at Week 12 or Week 16 in the CLOU064A2201, as well as participants who experienced a relapse during the 12-week observational period, were administered LOU064 50mg capsules b.i.d. (i.e. two capsules of LOU064 50mg in the morning and two capsules of LOU064 50mg in the evening) from Day 1 up to Week 52 of the Treatment period.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Participants must provide written informed consent prior to any assessments. * Participants must be willing and able to complete a daily symptom eDiary throughout the study and adhere to the study visit schedules. * Participants transitioning from the CLOU064A2201 trial must have completed either the Week 12 visit (end of treatment period) or the Week 16 visit (end of follow-up period). They will be assigned to either the treatment period or the observational period based on their UAS7 score (average score from the 7 days prior to the respective visit) as follows: 1. Participants transitioning at Week 12 of CLOU064A2201 with a UAS7 score of ≥16 will be allocated to the treatment period. 2. Participants transitioning at Week 16 of CLOU064A2201 with a UAS7 score of ≥16 will be allocated to the treatment period. 3. Participants transitioning at Week 16 of CLOU064A2201 with a UAS7 score of \<16 will be allocated to the observational period. Key
Exclusion criteria
* Participants with a clearly defined predominant or sole trigger for their chronic urticaria, such as chronic inducible urticaria (including symptomatic dermographism, cold-induced, heat-induced, solar-induced, pressure-induced, delayed pressure-induced, aquagenic-induced, cholinergic-induced, or contact-induced urticaria). * Participants with other diseases presenting with urticaria or angioedema symptoms, including but not limited to urticaria vasculitis, urticarial pigmentosa, erythema multiforme, mastocytosis, hereditary urticaria, or acquired/drug-induced urticaria. * Participants with any other skin disease associated with chronic itching that, in the opinion of the investigator, could affect the study evaluations and results, such as atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or psoriasis. * Participants with a history or current diagnosis of ECG abnormalities that indicate a significant safety risk for their participation in the study, including: * Concomitant clinically significant cardiac arrhythmias (e.g., sustained ventricular tachycardia) and clinically significant second or third-degree AV block without a pacemaker. * History of familiar long QT syndrome or a known family history of Torsades de Pointes. * Resting heart rate (as determined by physical exam or 12-lead ECG) below 50 bpm. * Resting QTcF interval ≥450 msec (in males) or ≥460 msec (in females) at day 1 of the treatment period or inability to determine the QTcF interval. * Use of agents known to prolong the QT interval, unless they can be permanently discontinued for the duration of the study. * Participants with a significant risk of bleeding or coagulation disorders. * Participants with a known or suspected history of an ongoing, chronic, or recurrent infectious disease, including but not limited to opportunistic infections (e.g., tuberculosis, atypical mycobacterioses, listeriosis, or aspergillosis), HIV, or Hepatitis B/C.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (AEs) | From first dose of treatment up to 28 days after last dose, assessed up to 56 weeks | An AE refers to any undesirable medical occurrence, such as an unintended sign (including abnormal laboratory findings), symptom, or disease, experienced by a participant. Serious AEs (SAEs) is defined as any AE that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or any other medically significant condition. Treatment-emergent AEs were defined as AEs that either begin on the same day or after the first dose of study medication during the treatment period in the extension study or worsen on the same day or after the first dose of study medication in the extension study and within the minimum of either 28 days post last dose or the end of the study visit. The number of participants with treatment-emergent AEs was summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 4 of the Treatment Period | Baseline, Week 4 of treatment period | 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 change from baseline in UAS7 at Week 4 of the treatment period was calculated. A negative change score from baseline indicates improvement. The UAS7 at baseline was considered as the UAS7 derived over the last 7 days before day 1 of the treatment period. |
| Percentage of Participants With Well-controlled Disease (UAS7≤6) at Week 4 of the Treatment Period | Week 4 of the treatment period | 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 values were imputed by non-responder imputation method regardless of the reason for missingness. The percentage of subjects with UAS7≤ 6 at Week 4 of the treatment period was calculated. The 90% confidence interval was derived based on the score method with continuity correction. |
| Percentage of Participants With Complete Response (UAS7=0) at Week 4 of the Treatment Period | Week 4 of the treatment period | 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 values were imputed by non-responder imputation method regardless of the reason for missingness. The percentage of subjects with UAS7= 0 at Week 4 of the treatment period was calculated. The 90% confidence interval was derived based on the score method with continuity correction. |
| Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime | From baseline until Week 52 of the treatment period | 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 with UAS7≤ 6 during the treatment period was calculated. The 90% confidence interval was derived based on the score method with continuity correction. The UAS7 at baseline was considered as the UAS7 derived over the last 7 days before day 1 of the treatment period. |
| Change From Baseline in UAS7 Overtime | From baseline until Week 52 of the treatment period | 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 change from baseline in UAS7 during the treatment period was calculated. A negative change score from baseline indicates improvement. The UAS7 at baseline was considered as the UAS7 derived over the last 7 days before day 1 of the treatment period. |
Countries
Argentina, Belgium, Canada, Czechia, Denmark, France, Hungary, Japan, Poland, Russia, Slovakia, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
229 subjects were enrolled in the observational period or the treatment period across 72 sites in 15 countries. One subject was a screening failure and, as a result, was not enrolled in either the observational or treatment period.
Pre-assignment details
Participants with UAS7\<16 at Week 16 of CLOU064A2201 (NCT03926611) entered a 12-week observational period. Participants with UAS7≥16 at Week 12 or Week 16 of CLOU064A2201, as well as those who relapsed during the observational period, entered the treatment period.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants with UAS7\<16 at Week 16 of CLOU064A2201 were followed up to 12 weeks without receiving treatment (observational period). If participants relapsed (UAS7≥16 at least once), they were transitioned to the treatment period.
Participants with a UAS7≥16 at Week 12 or Week 16 in the CLOU064A2201, as well as participants who experienced a relapse during the 12-week observational period, were administered 100 mg of LOU064 b.i.d. open-label for up to 52 weeks. | 229 |
| Total | 229 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | Covid-19 situation | 2 |
| Overall Study | Lack of Efficacy | 11 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Pregnancy | 1 |
| Overall Study | Subject Decision | 13 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 45 Years |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 44 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants |
| Race/Ethnicity, Customized White | 181 Participants |
| Sex: Female, Male Female | 165 Participants |
| Sex: Female, Male Male | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 194 |
| other Total, other adverse events | 0 / 68 | 56 / 194 |
| serious Total, serious adverse events | 1 / 68 | 6 / 194 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (AEs)
An AE refers to any undesirable medical occurrence, such as an unintended sign (including abnormal laboratory findings), symptom, or disease, experienced by a participant. Serious AEs (SAEs) is defined as any AE that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or any other medically significant condition. Treatment-emergent AEs were defined as AEs that either begin on the same day or after the first dose of study medication during the treatment period in the extension study or worsen on the same day or after the first dose of study medication in the extension study and within the minimum of either 28 days post last dose or the end of the study visit. The number of participants with treatment-emergent AEs was summarized.
Time frame: From first dose of treatment up to 28 days after last dose, assessed up to 56 weeks
Population: All subjects who received at least one dose of study treatment during the treatment period of this extension study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treated Cohort | Number of Participants With Treatment-emergent Adverse Events (AEs) | AEs | 139 Participants |
| Treated Cohort | Number of Participants With Treatment-emergent Adverse Events (AEs) | Deaths | 0 Participants |
| Treated Cohort | Number of Participants With Treatment-emergent Adverse Events (AEs) | Non-fatal Serious AEs (SAEs) | 6 Participants |
| Treated Cohort | Number of Participants With Treatment-emergent Adverse Events (AEs) | SAE(s) | 6 Participants |
| Treated Cohort | Number of Participants With Treatment-emergent Adverse Events (AEs) | Discontinued treatment due to any AE(s) | 11 Participants |
| Treated Cohort | Number of Participants With Treatment-emergent Adverse Events (AEs) | Discontinued treatment due to any SAE(s) | 2 Participants |
| Treated Cohort | Number of Participants With Treatment-emergent Adverse Events (AEs) | Treatment interruption due to AE(s) | 13 Participants |
| Treated Cohort | Number of Participants With Treatment-emergent Adverse Events (AEs) | Treatment interruption due to SAE(s) | 1 Participants |
Secondary
Change From Baseline in UAS7 Overtime
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 change from baseline in UAS7 during the treatment period was calculated. A negative change score from baseline indicates improvement. The UAS7 at baseline was considered as the UAS7 derived over the last 7 days before day 1 of the treatment period.
Time frame: From baseline until Week 52 of the treatment period
Population: Subjects who received at least one dose of study treatment during the treatment period of this extension study and did not have missing values at the specified time points. Number analyzed refers to the number of participants with an evaluable value at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treated Cohort | Change From Baseline in UAS7 Overtime | Week 1 | -14.76 Score on a Scale | Standard Deviation 11.502 |
| Treated Cohort | Change From Baseline in UAS7 Overtime | Week 4 | -17.58 Score on a Scale | Standard Deviation 13.4 |
| Treated Cohort | Change From Baseline in UAS7 Overtime | Week 12 | -19.37 Score on a Scale | Standard Deviation 12.502 |
| Treated Cohort | Change From Baseline in UAS7 Overtime | Week 20 | -20.61 Score on a Scale | Standard Deviation 11.634 |
| Treated Cohort | Change From Baseline in UAS7 Overtime | Week 28 | -21.54 Score on a Scale | Standard Deviation 11.525 |
| Treated Cohort | Change From Baseline in UAS7 Overtime | Week 40 | -21.25 Score on a Scale | Standard Deviation 11.4 |
| Treated Cohort | Change From Baseline in UAS7 Overtime | Week 52 | -21.82 Score on a Scale | Standard Deviation 10.699 |
Secondary
Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 4 of the Treatment Period
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 change from baseline in UAS7 at Week 4 of the treatment period was calculated. A negative change score from baseline indicates improvement. The UAS7 at baseline was considered as the UAS7 derived over the last 7 days before day 1 of the treatment period.
Time frame: Baseline, Week 4 of treatment period
Population: All subjects who received at least one dose of study treatment during the treatment period of this extension study with a value at both baseline and Week 4 of the treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treated Cohort | Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 4 of the Treatment Period | -17.58 Score on a Scale | Standard Deviation 13.4 |
Secondary
Percentage of Participants With Complete Response (UAS7=0) at Week 4 of the Treatment Period
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 values were imputed by non-responder imputation method regardless of the reason for missingness. The percentage of subjects with UAS7= 0 at Week 4 of the treatment period was calculated. The 90% confidence interval was derived based on the score method with continuity correction.
Time frame: Week 4 of the treatment period
Population: All subjects who received at least one dose of study treatment during the treatment period of this extension study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treated Cohort | Percentage of Participants With Complete Response (UAS7=0) at Week 4 of the Treatment Period | 27.3 Percentage of participants |
Secondary
Percentage of Participants With Well-controlled Disease (UAS7≤6) at Week 4 of the Treatment Period
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 values were imputed by non-responder imputation method regardless of the reason for missingness. The percentage of subjects with UAS7≤ 6 at Week 4 of the treatment period was calculated. The 90% confidence interval was derived based on the score method with continuity correction.
Time frame: Week 4 of the treatment period
Population: All subjects who received at least one dose of study treatment during the treatment period of this extension study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treated Cohort | Percentage of Participants With Well-controlled Disease (UAS7≤6) at Week 4 of the Treatment Period | 51.0 Percentage of participants |
Secondary
Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime
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 with UAS7≤ 6 during the treatment period was calculated. The 90% confidence interval was derived based on the score method with continuity correction. The UAS7 at baseline was considered as the UAS7 derived over the last 7 days before day 1 of the treatment period.
Time frame: From baseline until Week 52 of the treatment period
Population: All subjects who received at least one dose of study treatment during the treatment period of this extension study. Number analyzed refers to the number of participants with an evaluable value at the specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treated Cohort | Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime | Baseline | 1.0 Percentage of participants |
| Treated Cohort | Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime | Week 1 | 37.4 Percentage of participants |
| Treated Cohort | Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime | Week 4 | 52.7 Percentage of participants |
| Treated Cohort | Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime | Week 12 | 56.6 Percentage of participants |
| Treated Cohort | Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime | Week 20 | 62.7 Percentage of participants |
| Treated Cohort | Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime | Week 28 | 68.5 Percentage of participants |
| Treated Cohort | Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime | Week 40 | 66.5 Percentage of participants |
| Treated Cohort | Percentage of Participants With Well-controlled Disease (UAS7≤ 6) Overtime | Week 52 | 68.0 Percentage of participants |