Chronic Spontaneous Urticaria
Conditions
Brief summary
The first phase of this study will be a parallel, 12-week treatment, Phase 2, double-blind, 4 arm study to assess the safety and effectiveness of 3 oral doses of SAR444671 (rilzabrutinib), i.e. dose A, B and C, compared with placebo for decreasing the frequency and severity of itch and urticaria in male and female participants aged 18 years inclusive or older with CSU. After completion of the double-blind phase of the study, participants will be given the option of enrolling in the 40-week open label extension (OLE) phase of the study. Participants will receive open-label rilzabrutinib at dose B or dose C (the dose may be modified based on the 12-week safety and efficacy data). Due to the fact that some participants may be receiving rilzabrutinib for the first time, all participants will be monitored at Week 14, Week 16, Week 20, and Week 24. Afterwards, participants will be monitored at Week 36 and Week 52.
Interventions
DRUGplacebo
Tablet, oral use
DRUGrilzabrutinib
Tablet, oral use
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Participants who had a diagnosis of CSU refractory to H1-AH at the time of randomization * Diagnosis of CSU ≥3 months prior to screening visit (Visit 1). * The presence of itch and hives for ≥6 consecutive weeks at any time prior to screening visit (Visit 1) despite the use of H1-AH during this time period. * Participants using a study defined H1-AH for CSU treatment. For participants on stable doses of non-study-approved H1-AH, investigators may switch participants to an equivalent dose of a study-approved H1-AH maintenance medication. * Participants who were omalizumab naïve OR omalizumab-incomplete responders. * Participants must be willing and able to complete a daily symptom e-diary for the duration of the study. * During the 7 days before randomization: UAS7 ≥16 and ISS7 ≥8. * Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Exclusion criteria
* Clearly defined underlying etiology for CUs other than CSU (main manifestation being physical urticaria). * Presence of skin morbidities other than CSU that may interfere with the assessment of the study outcomes. * Participants with active atopic dermatitis (AD). * Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the patient's participation in the study. * Known or suspected immunodeficiency, or otherwise recurrent infections of abnormal frequency or prolonged duration suggesting an immune compromised status, as judged by the Investigator. * History of serious infections requiring intravenous (IV) therapy with the potential for recurrence (as judged by the Site Investigator) with less than 4 weeks interval between resolution of serious infection and first dose of study drug, or currently active moderate to severe infection at Screening (Grade 2 or higher), including active coronavirus disease 2019 (COVID-19). * Live vaccine except Bacille Calmette Guerin-vaccination within 28 days prior to Day 1 or plan to receive one during the trial; Bacille Calmette Guerin-vaccination within 12 months prior to Screening. * Active malignancy or history of malignancy within 5 years. * Conditions that may predispose the participant to excessive bleeding * Any participant with an uncontrolled disease state as judged by the Investigator, such as asthma, psoriasis, or inflammatory bowel disease, etc. that are typically treated with oral or parenteral corticosteroids * Previous use of a BTK inhibitor. * Had received any investigational drug (or is currently using an investigational device) within the 30 days before Day 1, or at least 5 times the respective elimination half-life time (whichever is longer). * Previous exposure to another investigative drug for CSU. * Positive for human immunodeficiency virus (HIV) antibody test. * Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with positive DNA test result at screening or within 3 months prior to the screening visit. * Positive hepatitis C antibody test result at screening or within 3 months prior to the screening visit. * Tuberculosis infection. * Any of significant laboratory abnormalities and ECG findings at the screening visit. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 12 | Baseline and Week 12 | The UAS7 score is a composite score containing both the hive severity score (HSS, ranging from 0 = None to 3 = more than 50 hives) and the itch severity score (ISS, ranging from 0 = None to 3 = intense). The daily UAS scores ranged from 0 to 6 points per day. Daily UAS scores were summed over a 7-day period to create the UAS7, ranging from 0 to 42, and are composed of the HSS7 and ISS7 components. A higher score indicates worse disease. Baseline is defined as the sum of the 7 days measurements obtained on and prior to the target visit day. |
| Change From Baseline in Weekly Itch Severity Score (ISS7) at Week 12 | Baseline and Week 12 | The ISS represents the itch severity on a scale and was recorded by the participant in their e-diary ranging from 0 (None) to 3 (intense). The ISS7 is the sum of ISS for the previous 7 days. The ISS7 represents itch severity on a scale ranging from 0 (minimum) to 21 (maximum). Higher scores indicate greater intensity of itch. Baseline is defined as the sum of the 7 days measurements obtained on and prior to the target visit day. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weekly Urticaria Activity Score at Week 4 | Baseline and Week 4 | The UAS7 score is a composite score containing both the hive severity score (HSS, ranging from 0 = None to 3 = more than 50 hives) and the itch severity score (ISS, ranging from 0 = None to 3 = intense). The daily UAS scores ranged from 0 to 6 points per day. Daily UAS scores were summed over a 7-day period to create the UAS7, ranging from 0 to 42, and are composed of the HSS7 and ISS7 components. A higher score indicates worse disease. Baseline is defined as the sum of the 7 measurements obtained within the 7 days prior to randomization. |
| Change From Baseline in Weekly Hives Severity Score (HSS7) at Week 12 | Baseline and Week 12 | The HSS7 represents hive severity score on a scale recorded on e-diary ranging from 0 (None) to 3 (more than 50 hives). A weekly score (HSS7) was sum of the average daily scores of the previous 7 days. The possible range of the weekly score was 0-21 (highest hives activity). Baseline is defined as the sum of the 7 days measurements obtained on and prior to the target visit day. |
| Percentage of Participants With Weekly Urticaria Activity Score Less Than or Equal to (≤)6 at Week 12 | At Week 12 | The UAS7 score is a composite score containing both the hive severity score (HSS, ranging from 0 = None to 3 = more than 50 hives) and the itch severity score (ISS, ranging from 0 = None to 3 = intense). The daily UAS scores ranged from 0 to 6 points per day. Daily UAS scores were summed over a 7-day period to create the UAS7, ranging from 0 to 42, and are composed of the HSS7 and ISS7 components. A higher score indicates worse disease. Here, a score ≤6 indicates well-controlled disease. |
| Percentage of Participants With Weekly Urticaria Activity Score Equal to 0 at Week 12 | At Week 12 | The UAS7 score is a composite score containing both the hive severity score (HSS, ranging from 0 = None to 3 = more than 50 hives) and the itch severity score (ISS, ranging from 0 = None to 3 = intense). The daily UAS scores ranged from 0 to 6 points per day. Daily UAS scores were summed over a 7-day period to create the UAS7, ranging from 0 to 42, and are composed of the HSS7 and ISS7 components. A higher score indicates worse disease. Here, score 0 indicates an absence of both itches and hives and a complete resolution of chronic spontaneous urticaria (CSU) symptoms. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Treatment-Emergent Adverse Events of Special Interest (AESIs), and Withdrawals Due to Treatment-Emergent Adverse Events | From first dose of study treatment (Day 1) up to last dose of study treatment + 7 days, approximately 13 weeks for DB period and approximately 41 weeks for OLE period | Adverse event (AE): any untoward medical occurrence in participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs: AEs that developed or worsened or became serious during treatment-emergent period, defined as time from first administration of study treatment (on Day 1) to last administration of study treatment + 7 days. SAE: any AE that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. An AESI was an TEAE (serious or nonserious) of scientific and medical concern specific to Sponsor's product or program. |
| Plasma Concentration of Rilzabrutinib | Pre-dose and 2 hours post-dose at Day 1 and Week 4; pre-dose at Week 12 (DB period); pre-dose and 2 hours post-dose at Week 16; pre-dose at Weeks 20, 24 and 52 (OLE period) | Plasma samples were collected at specified timepoints for evaluation of rilzabrutinib pharmacokinetic (PK) concentrations. |
Countries
Argentina, Canada, Chile, Germany, Greece, Italy, Japan, Netherlands, Poland, Russia, South Korea, Spain, Taiwan
Contacts
STUDY_DIRECTORClinical Sciences & Operations
Sanofi
Participant flow
Recruitment details
The study was conducted at 59 active centers in 13 countries. A total of 240 participants were screened between 24 November 2021 and 28 February 2023, of which 80 were screen failures. Screen failures were mainly due to not meeting the eligibility criteria.
Pre-assignment details
A total of 160 participants were enrolled in the study. Randomization was stratified by region and prior use of omalizumab.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 48.5 years STANDARD_DEVIATION 12.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 38 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 0 Participants |
| Race (NIH/OMB) White | 121 Participants |
| Sex: Female, Male Female | 112 Participants |
| Sex: Female, Male Male | 14 Participants |
| Weekly Itch Severity Score (ISS7) | 15.9 score on a scale STANDARD_DEVIATION 4.4 |
| Weekly Urticaria Activity Score (UAS7) | 30.3 score on a scale STANDARD_DEVIATION 7.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 38 | 0 / 41 | 0 / 41 | 0 / 9 | 0 / 128 |
| other Total, other adverse events | 14 / 40 | 20 / 38 | 26 / 41 | 25 / 41 | 7 / 9 | 59 / 128 |
| serious Total, serious adverse events | 1 / 40 | 0 / 38 | 0 / 41 | 2 / 41 | 1 / 9 | 4 / 128 |
Outcome results
None listed