A double-blind, randomized, placebo-controlled trial to evaluate the efficacy, pharmacokinetics and safety of remibrutinib (LOU064) for 24 weeks in adolescents from 12 to less than 18 years of age with chronic spontaneous urticaria inadequately controlled by H1-antihistamines followed by an optional open-label extension for up to another 3 years and an optional safety long-term treatment-free follow-up period for up to an additional 3 years.

The primary objective of this study is to assess the **efficacy** of remibrutinib compared to placebo in adolescents with **Chronic Spontaneous Urticaria** (CSU) by evaluating the absolute change from baseline in Urticaria Activity Score over 7 days (UAS7), Itch Severity Score over 7 days (ISS7), and Hives Severity Score over 7 days (HSS7) at Week 12. This is clinically relevant as it aims to determine the potential of remibrutinib to improve disease control in patients inadequately managed by H1-antihistamines.

Secondary objectives include: - Assessing pharmacokinetic parameters at Week 12. - Evaluating the proportion of participants achieving disease activity control (UAS7 ≤ 6) and complete absence of hives and itch (UAS7 = 0) at Week 12 and over time, comparing remibrutinib to placebo. - Evaluating the efficacy of remibrutinib versus placebo in CSU concerning changes from baseline in the Children's Dermatology Life Quality Index (CDLQI) score at Week 12. - Assessing the cumulative number of weeks between baseline and Week 12 during which subjects achieve an Angioedema Activity Score Over 7 Days equal to 0 (AAS7 = 0). - Assessing the safety and tolerability of remibrutinib over 24 weeks and during long-term treatment in the open-label extension (OLE) period.

The clinical trial involves a total of **57 participants** diagnosed with **Chronic Spontaneous Urticaria** (CSU). The study population comprises both male and female adolescents aged 12 to less than 18 years. Participants were selected based on specific criteria, including a CSU duration of at least six months prior to screening and inadequate control by second-generation H1-antihistamines. The trial includes individuals who have experienced itch and hives for at least six consecutive weeks before screening, with specific UAS7, ISS7, and HSS7 scores. The participants are considered a vulnerable population due to their age. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, pharmacokinetics, and safety of **remibrutinib** (LOU064) in adolescents aged 12 to less than 18 years with **chronic spontaneous urticaria** inadequately controlled by H1-antihistamines. The trial consists of a 24-week core period followed by an optional open-label extension for up to three years and an optional safety long-term treatment-free follow-up period for an additional three years. The primary objective is to assess the efficacy of remibrutinib versus placebo with respect to the absolute change from baseline in UAS7, ISS7, and HSS7 at Week 12. Secondary endpoints include the concentration of remibrutinib at Week 12, achievement of UAS7 ≤ 6 and UAS7 = 0, and the occurrence of treatment-emergent adverse events.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, duration of **chronic spontaneous urticaria**, and inadequate control by second-generation H1-antihistamines. Follow-up visits will occur throughout the 24-week core period to monitor efficacy and safety parameters, including laboratory tests and vital signs. The end-of-study visit will conclude the core period, with the option for participants to enter the open-label extension phase. The expected length of participant involvement in the core period is 24 weeks, with the potential for extended participation in the open-label and follow-up phases. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or withdrawal of consent by the participant.

The clinical trial involves the administration of **remibrutinib**, marketed under the product code LOU064, as the primary experimental medication. Remibrutinib is a low molecular weight compound that covalently binds and inhibits Bruton’s tyrosine kinase. It is provided in the form of a film-coated tablet, with a maximum daily dose of 50 mg and a total maximum dose of 33,600 mg over a treatment period of 96 weeks. The route of administration is oral, and the medication is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental medication, the trial includes a **placebo** group. The placebo is designed to match the LOU064 25 mg and 10 mg film-coated tablets in appearance but contains no active substance. The placebo is administered orally, and its use is intended to provide a control for evaluating the efficacy of remibrutinib.

As part of the auxiliary treatments, **antihistamines** are used to block histamine release from histamine-1 receptors. These are administered orally, with a maximum treatment period of 42 days. The specific dosage and frequency are not detailed, as they are considered standard-of-care therapy for participants with chronic spontaneous urticaria.

Additionally, **corticosteroids for systemic use, plain** are included as auxiliary treatment. These corticosteroids exert anti-inflammatory effects by influencing multiple signal transduction pathways. They are administered orally, with a maximum treatment period of 30 days. The dosage form and specific dosing schedule are not specified, as they are auxiliary to the primary treatment.

The efficacy of remibrutinib in the treatment of chronic spontaneous urticaria (CSU) will be assessed through several primary and secondary endpoints. The primary endpoint is the absolute change from baseline in the **Urticaria Activity Score over 7 days (UAS7)**, **Itch Severity Score over 7 days (ISS7)**, and **Hives Severity Score over 7 days (HSS7)** at Week 12. These scores are used to evaluate the severity and frequency of symptoms associated with CSU.

Secondary endpoints include the concentration of remibrutinib at Week 12, including Cmax, Tmax, and AUC, as well as the absolute change from baseline in UAS7 at Week 12. Additional secondary endpoints involve the achievement of UAS7 ≤ 6 and UAS7 = 0 at Week 12 and over time, the absolute change from baseline in the **Children's Dermatology Life Quality Index (CDLQI)** score at Week 12, and the number of weeks without angioedema, assessed by the cumulative number of weeks with an **Angioedema Activity Score over 7 days (AAS7)** = 0 response between baseline and Week 12. The occurrence of treatment-emergent adverse events (AEs), serious adverse events (SAEs), and laboratory and vital signs abnormalities during the core and open-label extension (OLE) periods will also be monitored.

These efficacy parameters will be measured and collected at specified timepoints, including baseline and Week 12, using validated scales and laboratory tests. The analysis will focus on comparing the changes in these scores and concentrations from baseline to Week 12 to determine the efficacy of remibrutinib in managing CSU symptoms.