A randomized, double-blind, placebo-controlled, multi-center, dose-ranging Phase 2 study of rilzabrutinib followed by an open-label extension phase in patients with moderate-to-severe chronic spontaneous urticaria (CSU) who remain symptomatic despite the use of H1 antihistamine treatment

Participants who have 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 are 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.

Participants are excluded from the study if any of the following criteria apply:
- 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 and the Sponsor
Medical Monitor) 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.
- Has 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