Estudo do Remibrutinibe (Lou064) Eficácia e Segurança e Exploração de seu mecanismo de ação em participantes com urticária crônica

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.

2. Male and female participants ≥ 18 years of age at the time of signing of the informed consent forms.

3. CINDU patients: Confirmed diagnosis of CINDU with a duration of ≥ 4 months (defined as onset of CINDU with supporting documentation (e.g. medical record, clinical history, photographs) and inadequate control with H1-AH at local label approved doses at the time of randomization. The response to the provocation test for each CINDU subtype is required before randomization (either during screening or prior to randomization on Day 1):

4. CINDU patients: Patients should be symptomatic for their most bothersome symptom as assessed with the USDD during baseline with a NRS score of 3 or more

5. CSU patients: Diagnosis of CSU (acc. to Zuberbier et al 2022c) not adequately controlled with H1-AH at approved doses alone for at least 4 weeks prior to randomization, as defined by all of the following:

   • UAS7 score (range 0-42) ≥ 16 and HSS7 (range 0-21) ≥ 8 during 7 days prior to randomization
   • CSU for ≥ 6 months

6. Participants must be willing and able to attend the protocol defined test procedure throughout the study.

Exclusion Criteria:

1. Participants who have a familial/hereditary form (e.g. familial cold autoinflammatory syndrome, familial cold urticaria) of the target CINDU that is being considered for the participant's inclusion in this study.

2. Diseases, other than CSU or CINDU, with urticaria or angioedema symptoms including but not limited to:

   • urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa),
   • food allergies yielding urticaria symptoms when the allergen is not avoided by the dietary habits of the participant
   • hereditary or acquired angioedema.

3. CINDU patients only: To prevent any confounding effect of CSU symptoms, the CINDU study population will consist of participants with predominant CINDU and should not have a significant share of CSU symptoms (that might make the assessment of CINDU symptoms difficult) as per the investigator's judgement.

4. CSU patients only: Patients should have no relevant inducible urticaria trigger

5. Any other skin disease associated with chronic itching that might influence, in the investigator's opinion, the study evaluations and results (e.g., atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, etc.) or skin diseases associated with only wheals and no itch e.g asymptomatic dermographism

6. Known or suspected ongoing, chronic or recurrent infectious disease including but not limited to opportunistic infections (e.g., tuberculosis, atypical mycobacterioses, listeriosis or aspergillosis) and/or known positivity for Human Immunodeficiency Virus (HIV) infection.

7. Evidence of an ongoing Hepatitis C infection (defined by the detection at screening of Hepatitis C virus antibodies (anti-HCVAb) and hepatitis C ribonucleic acid (HCV-RNA) in participants who are positive for anti-HCVAb) and/or an ongoing Hepatitis B infection (defined by the detection of Hepatitis B virus surface antigen (HBsAg) and/or hepatitis B virus (HBV)-DNA at screening; participants who are positive for anti-hepatitis B core (HBc) antibodies but who are negative for antibodies against HBsAg and HBV-DNA can be included into the study if they agree to monitoring for HBsAg and HBV-DNA reactivation).

8. Major surgery within 8 weeks prior to screening or planned surgery for the duration of the study.

9. Evidence of clinically significant cardiovascular (such as but not limited to myocardial infarction, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, arrhythmia and uncontrolled hypertension within 12 months prior to Screening), 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.

10. Uncontrolled disease states, such as asthma, or inflammatory bowel disease, or any other disease where flares are commonly treated with oral or parenteral corticosteroids.

11. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years (except for basal cell carcinoma or actinic keratosis that have been treated with no evidence of recurrence in the past 3 months, carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed).

12. History or presence of impaired renal function as indicated by clinically significantly abnormal creatinine or BUN values, or abnormal urinary constituents (e.g. proteinuria, hematuria)

    • Evidence of urinary obstruction, or difficulty in voiding at screening
    • Evidence of congenital renal abnormalities with known effect on renal function
    • Calculated eGFR < 60 mL/min

13. Hematology parameters at screening:

    • Hemoglobin: < 10 g/dL
    • Platelets: < 100,000/mm3
    • Leucocytes: < 3,000/mm3
    • Neutrophils:< 1,500/mm3

14. History or current hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure or Aspartate Aminotransferase (AST)/ Alanine Aminotransferase (ALT) levels of more than 1.5 x upper limit of normal (ULN) or International Normalized Ratio (INR) of more than 1.5 at screening

15. Use of other investigational drugs s within 5 half-lives or within 30 days (for small molecules) prior to Screening or until the expected pharmacodynamic (PD) effect has returned to baseline (for biologics), whichever is longer; or longer if required by local regulations

16. Contraindications to or hypersensitivity to remibrutinib (or its excipients or to drugs of similar chemical classes) or other substances provided to the subjects as rescue medication to control symptoms, such as antihistamines.

17. Participants taking prohibited therapies as listed in Section 6.6.2. In particular patients with pretreatment with remibrutinib or another BTK-inhibitor within 4 months prior to randomization.

18. History of live or live attenuated vaccine within 6 weeks prior to randomization or requirement to receive these vaccinations at any time during the study drug treatment.

19. Requirement for anti-platelet medication, except for acetylsalicylic acid up to 100 mg/d or clopidogrel up to 75 mg/d which are allowed. The use of dual anti-platelet therapy (e.g., acetylsalicylic acid + clopidogrel) is prohibited.

20. Requirement for anticoagulant medication (for example, warfarin or Novel Oral Anti-Coagulants (NOAC)).

21. History of gastrointestinal bleeding, e.g., in association with use of nonsteroidal anti-inflammatory drugs (NSAID), that was clinically relevant (e.g., where intervention was indicated or requiring hospitalization or blood transfusion)

22. Significant bleeding risk or coagulation disorders.

23. Known history or evidence of ongoing alcohol or drug abuse within the last 6 months before randomization as per source records.

24. Pregnant or nursing (breast feeding) women.

25. Women of child-bearing potential, defined as fertile, following menarche and until becoming post-menopausal unless they are permanent sterile or they are using highly effective methods of contraception during dosing for 7 days after stopping study treatment. Highly effective contraception methods include:

    • Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Note that periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Bilateral oophorectomy with or without hysterectomy, total hysterectomy or bilateral salpingectomy at least six weeks prior to the first dose of study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered to be not of child-bearing potential.
    • Bilateral tubal occlusion, Bilateral tubal ligation (at least six weeks prior to the first dose of study treatment)
    • Male partner sterilization (vasectomy) of male partner(s) of the female participant at least six months prior to screening). The vasectomized male partner should be sole partner for that participant and received medical assessment of the surgical success.
    • Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.

The decision on the contraceptive method should be reviewed at least every 3 months to evaluate the individual need and compatibility of the method chosen. In case of use of hormonal contraception, women should have been stable on the same method for a minimum of 3 months before taking study treatment. Women are considered post-menopausal if they have no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Women are considered not of child-bearing potential if they are post-menopausal or permanently sterileor have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral salpingectomy at least six weeks prior to first dose of study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child-bearing potential.

If local regulations are more stringent than the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.