An Extension Study of Long-term Efficacy, Safety and Tolerability of Remibrutinib in Chronic Spontaneous Urticaria Patients Who Completed Preceding Studies With Remibrutinib

Study Overview
=================
Brief Summary
-----------------
The purpose of this extension study is to collect long-term efficacy, safety and tolerability data on remibrutinib in a selected group of participants with Chronic Spontaneous Urticaria (CSU) who previously completed the treatment phase of remibrutinib preceding Phase 3 studies. This study will also fulfill the Novartis commitment to provide post-trial access to participants who have completed the preceding Phase 3 studies, where applicable.

Detailed Description
-----------------
This is a global, multicenter, randomized, double-blind, placebo-controlled, randomized withdrawal Phase 3b extension study, followed by long-term open label treatment cycles to assess the efficacy, safety and tolerability of remibrutinib in adult participants with CSU inadequately controlled by H1-AH. The study comprises 2 Epochs. Epoch 1 is the initial study period for participants who completed preceding remibrutinib Phase 3 studies. Epoch 1 comprises of a 24-week randomized withdrawal period with remibrutinib or placebo for patients with UAS7<16 OR a 24 week Open-label treatment period with remibrutinib for patients with UAS7≥16. Participants will be randomized in a 1:1 ratio to enter the double-blind placebo-controlled 24-week withdrawal phase. In case of relapse (UAS7≥16) in the blinded group, participants enter the (Re-)treatment period Epoch 1 and receive 24 weeks of Open-label treatment with remibrutinib. At the end of the (Re-)treatment period Epoch 1, participants will move to Epoch 2. Epoch 2 is the second subsequent study period and consists of 24-week cycles that could either encompass treatment-free Observation and/or Open-label (Re-)treatment periods with remibrutinib, with or without background H1-AH. In case of relapse (UAS7≥16) during an Observation period, participants enter the next (Re-)treatment period and receive 24 weeks of treatment with remibrutinib. Participants completing an Observation period 2/3/4/5 with a UAS7≤6 will complete the study. Participants with a UAS7 >6 -<16 can enter the next (Re-)treatment period if continuous treatment is considered necessary and beneficial for the individual participant. For participants with a UAS7<16 that enter the next (Re-)treatment period, remibrutinib monotherapy treatment (without background H1-AH) is required.

Official Title
-----------------
A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal and Open-label Extension Study Followed by Long-term Open-label Treatment Cycles to Assess the Efficacy, Safety and Tolerability of Remibrutinib (LOU064) in Adult Chronic Spontaneous Urticaria Patients Who Completed the Preceding Remibrutinib Phase 3 Studies

Conditions
-----------------
Chronic Spontaneous Urticaria

Intervention / Treatment
-----------------
* Drug: LOU064 (blinded)
* Drug: Placebo
* Drug: LOU064 (open label)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent must be obtained before any assessment is performed. Male and female, adult participants ≥18 years of age. Participants who successfully completed the preceding core studies CLOU064A2301, CLOU064A2302, CLOU064A1301, CLOU064A2304 or CLOU064A2305 according to the respective protocols. Willing and able to adhere to the study protocol and visit schedule. Exclusion Criteria: Significant bleeding risk or coagulation disorders. History of gastrointestinal bleeding. Requirement for anti-platelet medication. Requirement for anticoagulant medication. History or current hepatic disease. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: LOU064 (blinded)<br>LOU064 (blinded) taken orally for 24 weeks, followed by cycles of either LOU064 (open-label) taken orally for a maximum of 5 cycles of 24 weeks each OR treatment-free observation cycles. Randomized in a 1:1 ratio (arm 1:arm 2) | Drug: LOU064 (blinded)<br>* LOU064 (blinded) active treatment<br>* Other names: remibrutinib;Drug: LOU064 (open label)<br>* LOU064 (open-label) active treatment<br>* Other names: remibrutinib;|
| Placebo Comparator: Arm 2: LOU064 Placebo (blinded)<br>LOU064 placebo (blinded) taken orally for 24 weeks, followed by cycles of either LOU064 (open-label) taken orally for a maximum of 5 cycles of 24 weeks each OR treatment-free observation cycles. Randomized in a 1:1 ratio (arm 1:arm 2) | Drug: Placebo<br>* Placebo<br>Drug: LOU064 (open label)<br>* LOU064 (open-label) active treatment<br>* Other names: remibrutinib;|
| Experimental: Arm 3: LOU064 (Open Label)<br>LOU064 (open-label) taken orally for 24 weeks per treatment cycle (Arm 3) | Drug: LOU064 (open label)<br>* LOU064 (open-label) active treatment<br>* Other names: remibrutinib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first composite event (i.e., relapse (UAS7≥16) | The efficacy of remibrutinib in CSU participants with a UAS7<16 at Week 52 in the prior core study with respect to time to first of the three events: relapse or study treatment discontinuation due to lack of efficacy or intake of strongly confounding prohibited medication up to Week 24 compared to placebo. (Epoch 1) Time to first composite event (i.e., relapse (UAS7≥16), study treatment discontinuation due to lack of efficacy or intake of strongly confounding prohibited medication) during the randomized withdrawal period (Epoch 1) Urticaria Activity Score (UAS7) describes the number of hives with 0 being No Hives and 3 is most severe. The final score is calculated by adding together daily scores which can range from 0-6 for 7 days. The resulting maximum score is then 42. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent (serious and non-serious) adverse events | Occurrence of treatment-emergent (serious and non-serious) adverse events | 160 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CSU, Brutons Tyrosine Kinase (BTK) inhibitor, Chronic Spontaneous Urticaria, Urticaria activity score, Hives severity score, Itch severity score, Extension, Randomized withdrawal, Retreatment upon relapse, Remibrutinib