Chronic Spontaneous Urticaria
Conditions
Keywords
Chronic Spontaneous Urticaria (CSU), remibrutinib, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Ambulator Blood Pressure Monitoring (ABPM), H1 antihistamines (H1-AH) treatment
Brief summary
The purpose of this study was to assess the effect of remibrutinib 25 mg twice a day (b.i.d.) open-label on Systolic Blood Pressure (SBP) measured as a change in 24-hour weighted average SBP from baseline to Week 4 assessed by Ambulator Blood Pressure Monitoring (ABPM); and to assess overall safety and efficacy over 12 weeks in adult participants with Chronic Spontaneous Urticaria (CSU) inadequately controlled with second generation H1 antihistamines (H1-AH) treatment. ABPM was chosen for the blood pressure assessment in this trial as recommended by the FDA for drugs intended for chronic use (Assessment of Pressor Effects of Drugs Guidance for Industry (FDA 2022)).
Detailed description
This study consisted of a screening period of up to 4 weeks, a 12-week open-label treatment period and a treatment-free follow-up period of 4 weeks, with a total study duration of up to 20 weeks. At the end of the treatment phase, participants had the option to continue in an extension study (CLOU064A2303B (NCT05513001)) if approved in the country and at the site.
Interventions
DRUGLOU064
One film-coated tablet (25 mg) was to be taken in the morning and evening, respectively, with a 12-hour interval at approximately the same time everyday.
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: * Signed informed consent obtained prior to participation in the study * Male and female adult participants \>= 18 years of age * CSU duration for \>= 6 months prior to screening (defined as the onset of CSU determined by the Investigator based on all available supporting documentation). * Diagnosis of CSU inadequately controlled by second generation H1-AH at the time of baseline (Day 1) * Documentation of hives within three months before baseline (either at screening and/or at baseline (Day 1); or documented in the participants' medical history). * Willing and able to complete an Urticaria Patient Daily Diary (UPDD) for the duration of the study and adhere to the protocol * Participants had no more than 2 missing UPDD entries (either morning or evening) in the 7 days prior to baseline (Day 1). Key
Exclusion criteria
* Participants unable to tolerate 24-hour ambulatory blood pressure measurement using automatic ABPM device * Ongoing or past history of hypertension and/or SBP \>= 140 or =\< 90 OR DBP \>= 90 or =\< 60 mmHg at screening * Participants working night shifts * Participants taking/requiring medications prohibited by the protocol (including those known to interfere with blood pressure assessments in the study) * Evidence of clinically significant cardiovascular, neurological, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic, hematological disorders, gastrointestinal disease or immunodeficiency that, in the Investigator's opinion, would compromise the safety of the participant, interfere with the interpretation of the study results or otherwise preclude participation or protocol adherence of the participant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Mean Change From Baseline at Week 4 in 24-hour Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM) | Baseline, Week 4 | A linear regression with SBP as a covariate was employed. The change in SBP from baseline to Week 4 was predicted at the median baseline level. The change from baseline in the 24-hour weighted average SBP was calculated using the time weighted average of the area under the curve (AUC) of SBP obtained over a 24-hour period as measured by ABPM. That is, the time weighted average of AUC of 24-hour SBP obtained at baseline was subtracted from corresponding time weighted average of AUC of SBP at Week 4. In the analysis, if participants took prohibited antihypertensive treatment before Week 4, their subsequent measurements were excluded. In such cases, the excluded measurements were imputed by increasing the 24-hour SBP by 3 mmHg from the baseline value at Week 4. Moreover, participants who discontinued of study treatment due to any reason prior to the Week 4 were excluded from the analysis. The Mixed Models for Repeated Measures (MMRM) approach was used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Observed Mean Change From Baseline to Week 4 in 24-hour Weighted Average Systolic Blood Pressure (SBP) Measured by ABPM | Baseline, Week 4 | The change from baseline in the 24-hour weighted average systolic blood pressure (SBP) was calculated using the time weighted average of the area under the curve (AUC) of SBP obtained over a 24-hour period as measured by ABPM. This analysis was conducted using the observed data. Data was computed taking weighted averages over time and discarding time intervals of more than 1 hour without measurements. |
| Estimated Mean Change From Baseline at Week 4 in 24-hour Diastolic Blood Pressure (DBP) Measured by ABPM | Baseline, Week 4 | A linear regression with DBP as a covariate was employed. The change in DBP from baseline to Week 4 was predicted at the median baseline level. The change from baseline in the 24-hour weighted average DBP was calculated using the time weighted average of the area under the curve (AUC) of DBP obtained over a 24-hour period as measured by ABPM. That is, the time weighted average of AUC of 24-hour DBP obtained at baseline was subtracted from corresponding time weighted average of AUC of DBP at Week 4. In the analysis, if participants took prohibited antihypertensive treatment before Week 4, their subsequent measurements were excluded. In such cases, the excluded measurements were imputed by increasing the 24-hour DBP by 3 mmHg from the baseline value at Week 4. Moreover, participants who discontinued of study treatment due to any reason prior to the Week 4 were excluded from the analysis. The Mixed Models for Repeated Measures (MMRM) approach was used. |
| Estimated Mean Change From Baseline at Week 4 in Daytime and Nighttime Average SBP Measured by ABPM | Baseline, Week 4 | The change in daytime (respectively nighttime) weighted average SBP was analyzed using linear regression model with baseline weighted average daytime SBP (respectively nighttime) as a covariate. The change in daytime (respectively nighttime) SBP from baseline to Week 4 was predicted at the median baseline level. The change from baseline of daytime (respectively nighttime) SBP was calculated using the time weighted average of the AUC of DBP obtained over daytime (respectively nighttime) In the analysis, if participants took prohibited antihypertensive treatment before Week 4, their subsequent measurements were excluded. In such cases, the excluded measurements were imputed by increasing the 24-hour SBP by 3 mmHg from the baseline value at Week 4. Moreover, participants who discontinued of study treatment due to any reason prior to the Week 4 were excluded from the analysis. The multiple imputation approach was used. Daytime: from 7am until 10 pm. Nighttime: from 10pm until 7 am. |
| Estimated Mean Change From Baseline at Week 4 in Daytime and Nighttime Average DBP Measured by ABPM | Baseline, Week 4 | The change in daytime (respectively nighttime) weighted average DBP was analyzed using linear regression model with baseline weighted average daytime DBP (respectively nighttime) as a covariate. The change in daytime (respectively nighttime) DBP from baseline to Week 4 was predicted at the median baseline level. The change from baseline of daytime (respectively nighttime) DBP was calculated using the time weighted average of the AUC of DBP obtained over daytime (respectively nighttime) In the analysis, if participants took prohibited antihypertensive treatment before Week 4, their subsequent measurements were excluded. In such cases, the excluded measurements were imputed by increasing the 24-hour DBP by 3 mmHg from the baseline value at Week 4. Moreover, participants who discontinued of study treatment due to any reason prior to the Week 4 were excluded from the analysis. The multiple imputation approach was used. Daytime: from 7am until 10 pm. Nighttime: from 10pm until 7 am. |
Countries
Argentina, Canada, France, Germany, Singapore, Slovakia, South Korea, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
This study was conducted globally across 10 countries: Argentina (4 centers), Canada (2 centers), France (8 centers), Germany (6 centers), Republic of Korea (3 centers), Singapore (1 center), Slovakia (3 centers), Spain (4 centers), Turkey (3 centers), and USA (11 centers).
Pre-assignment details
Participants underwent a screening period of up to 4 weeks.
Participants by arm
| Arm | Count |
|---|---|
| LOU064 (Remibrutinib) All participants were assigned to remibrutinib 25 mg b.i.d. for 12 weeks. | 144 |
| Total | 144 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Subject decision | 2 |
| Overall Study | Unsatisfactory therapeutic effect | 2 |
Baseline characteristics
| Characteristic | LOU064 (Remibrutinib) |
|---|---|
| Age, Continuous | 42.2 Years STANDARD_DEVIATION 14.52 |
| Baseline Diastolic Blood Pressure (DBP) | 75.0 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.98 |
| Baseline Systolic Blood Pressure (SBP) | 117.1 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.11 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 19 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 32 Participants |
| Race (NIH/OMB) White | 89 Participants |
| Sex: Female, Male Female | 105 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 144 |
| other Total, other adverse events | 32 / 144 |
| serious Total, serious adverse events | 4 / 144 |
Outcome results
Primary
Estimated Mean Change From Baseline at Week 4 in 24-hour Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM)
A linear regression with SBP as a covariate was employed. The change in SBP from baseline to Week 4 was predicted at the median baseline level. The change from baseline in the 24-hour weighted average SBP was calculated using the time weighted average of the area under the curve (AUC) of SBP obtained over a 24-hour period as measured by ABPM. That is, the time weighted average of AUC of 24-hour SBP obtained at baseline was subtracted from corresponding time weighted average of AUC of SBP at Week 4. In the analysis, if participants took prohibited antihypertensive treatment before Week 4, their subsequent measurements were excluded. In such cases, the excluded measurements were imputed by increasing the 24-hour SBP by 3 mmHg from the baseline value at Week 4. Moreover, participants who discontinued of study treatment due to any reason prior to the Week 4 were excluded from the analysis. The Mixed Models for Repeated Measures (MMRM) approach was used.
Time frame: Baseline, Week 4
Population: Full Analysis Set (FAS): all participants to whom study treatment was assigned and received at least one dose of treatment. Participants who discontinued treatment prior to Week 4 were excluded from the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LOU064 (Remibrutinib) | Estimated Mean Change From Baseline at Week 4 in 24-hour Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM) | -1.3 millimeter of mercury (mmHg) |
Secondary
Estimated Mean Change From Baseline at Week 4 in 24-hour Diastolic Blood Pressure (DBP) Measured by ABPM
A linear regression with DBP as a covariate was employed. The change in DBP from baseline to Week 4 was predicted at the median baseline level. The change from baseline in the 24-hour weighted average DBP was calculated using the time weighted average of the area under the curve (AUC) of DBP obtained over a 24-hour period as measured by ABPM. That is, the time weighted average of AUC of 24-hour DBP obtained at baseline was subtracted from corresponding time weighted average of AUC of DBP at Week 4. In the analysis, if participants took prohibited antihypertensive treatment before Week 4, their subsequent measurements were excluded. In such cases, the excluded measurements were imputed by increasing the 24-hour DBP by 3 mmHg from the baseline value at Week 4. Moreover, participants who discontinued of study treatment due to any reason prior to the Week 4 were excluded from the analysis. The Mixed Models for Repeated Measures (MMRM) approach was used.
Time frame: Baseline, Week 4
Population: FAS: all participants to whom study treatment was assigned and received at least one dose of treatment. Participants who discontinued treatment prior to Week 4 were excluded from the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LOU064 (Remibrutinib) | Estimated Mean Change From Baseline at Week 4 in 24-hour Diastolic Blood Pressure (DBP) Measured by ABPM | -0.1 millimeter of mercury (mmHg) |
Secondary
Estimated Mean Change From Baseline at Week 4 in Daytime and Nighttime Average DBP Measured by ABPM
The change in daytime (respectively nighttime) weighted average DBP was analyzed using linear regression model with baseline weighted average daytime DBP (respectively nighttime) as a covariate. The change in daytime (respectively nighttime) DBP from baseline to Week 4 was predicted at the median baseline level. The change from baseline of daytime (respectively nighttime) DBP was calculated using the time weighted average of the AUC of DBP obtained over daytime (respectively nighttime) In the analysis, if participants took prohibited antihypertensive treatment before Week 4, their subsequent measurements were excluded. In such cases, the excluded measurements were imputed by increasing the 24-hour DBP by 3 mmHg from the baseline value at Week 4. Moreover, participants who discontinued of study treatment due to any reason prior to the Week 4 were excluded from the analysis. The multiple imputation approach was used. Daytime: from 7am until 10 pm. Nighttime: from 10pm until 7 am.
Time frame: Baseline, Week 4
Population: FAS: all participants to whom study treatment was assigned and received at least one dose of treatment. Participants who discontinued treatment prior to Week 4 were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| LOU064 (Remibrutinib) | Estimated Mean Change From Baseline at Week 4 in Daytime and Nighttime Average DBP Measured by ABPM | daytime average DBP | -0.6 millimeter of mercury (mmHg) |
| LOU064 (Remibrutinib) | Estimated Mean Change From Baseline at Week 4 in Daytime and Nighttime Average DBP Measured by ABPM | nighttime average DBP | 0.2 millimeter of mercury (mmHg) |
Secondary
Estimated Mean Change From Baseline at Week 4 in Daytime and Nighttime Average SBP Measured by ABPM
The change in daytime (respectively nighttime) weighted average SBP was analyzed using linear regression model with baseline weighted average daytime SBP (respectively nighttime) as a covariate. The change in daytime (respectively nighttime) SBP from baseline to Week 4 was predicted at the median baseline level. The change from baseline of daytime (respectively nighttime) SBP was calculated using the time weighted average of the AUC of DBP obtained over daytime (respectively nighttime) In the analysis, if participants took prohibited antihypertensive treatment before Week 4, their subsequent measurements were excluded. In such cases, the excluded measurements were imputed by increasing the 24-hour SBP by 3 mmHg from the baseline value at Week 4. Moreover, participants who discontinued of study treatment due to any reason prior to the Week 4 were excluded from the analysis. The multiple imputation approach was used. Daytime: from 7am until 10 pm. Nighttime: from 10pm until 7 am.
Time frame: Baseline, Week 4
Population: FAS: all participants to whom study treatment was assigned and received at least one dose of treatment. Participants who discontinued treatment prior to Week 4 were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| LOU064 (Remibrutinib) | Estimated Mean Change From Baseline at Week 4 in Daytime and Nighttime Average SBP Measured by ABPM | daytime average SBP | -1.2 millimeter of mercury (mmHg) |
| LOU064 (Remibrutinib) | Estimated Mean Change From Baseline at Week 4 in Daytime and Nighttime Average SBP Measured by ABPM | nighttime average SBP | -0.9 millimeter of mercury (mmHg) |
Secondary
Observed Mean Change From Baseline to Week 4 in 24-hour Weighted Average Systolic Blood Pressure (SBP) Measured by ABPM
The change from baseline in the 24-hour weighted average systolic blood pressure (SBP) was calculated using the time weighted average of the area under the curve (AUC) of SBP obtained over a 24-hour period as measured by ABPM. This analysis was conducted using the observed data. Data was computed taking weighted averages over time and discarding time intervals of more than 1 hour without measurements.
Time frame: Baseline, Week 4
Population: Full Analysis Set (FAS): all participants to whom study treatment was assigned and received at least one dose of treatment. Only participants with a value at both baseline and Week 4 were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LOU064 (Remibrutinib) | Observed Mean Change From Baseline to Week 4 in 24-hour Weighted Average Systolic Blood Pressure (SBP) Measured by ABPM | -1.65 millimeter of mercury (mmHg) | Standard Deviation 6.905 |