This Was a Dose-finding Study to Evaluate Efficacy and Safety of LOU064 in Patients With CSU Inadequately Controlled by H1-antihistamines

Study Overview
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Brief Summary
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This was a multicenter, randomized, double-blind and placebo-controlled phase 2b dose-finding study to assess the efficacy and safety of LOU064 in adults chronic spontaneous urticaria (CSU) patients inadequately controlled by H1-antihistamines

Detailed Description
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This was a global Phase 2b multicenter, randomized, double-blind, parallel-group, placebo-controlled study investigating the efficacy, safety and tolerability of six dosing groups of oral LOU064 in subjects with inadequately controlled CSU despite treatment with (second generation) H1-antihistamine. The study comprised of the 7 treatment arms: LOU064 10 mg q.d., LOU064 35 mg q.d., LOU064 100 mg q.d., LOU064 10 mg b.i.d, LOU064 25 mg b.i.d., LOU064 100 mg b.i.d. and placebo.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo- Controlled Phase 2b Dose-finding Study to Investigate the Efficacy, Safety and Tolerability of LOU064 in Adult Chronic Spontaneous Urticaria (CSU) Patients Inadequately Controlled by H1-antihistamines

Conditions
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Chronic Spontaneous Urticaria

Intervention / Treatment
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* Drug: LOU064 Arm 1
* Drug: LOU064 Arm 2
* Drug: LOU064 Arm 3
* Drug: LOU064 Arm 4
* Drug: LOU064 Arm 5
* Drug: LOU064 Arm 6
* Drug: Placebo arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects aged ≥18 years of age CSU diagnosis for ≥ 6 months prior to screening Presence of itch and hives for ≥6 consecutive weeks prior to screening in spite of use of non-sedating H1-antihistamines according to local Treatment guidelines during this time period UAS7 score (range 0-42) ≥16 and HSS7 score (range 0-21) ≥ 8 during 7 days prior to randomization (Day 1) Willing and able to complete an Urticaria Participant Daily eDiary (UPDD) for the duration of the study Exclusion Criteria: Hypersensitivity to any of the study treatments Clearly defined predominant or sole trigger of their chronic urticaria (chronic inducible urticaria) Other diseases with symptoms of urticaria or angioedema Other skin disease associated with chronic itching that might influence in the investigators opinion the study evaluations and results, Known or suspected history of an ongoing, chronic or recurrent infectious disease including but not limited to opportunistic infections (eg tuberculosis, atypical mycobacterioses, listeriosis or aspergillosis), HIV, Hepatitis B/C. Pregnant or nursing (lactating) women Women of child-bearing potential not using highly effective methods of contraception

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This was a global Phase 2b multicenter, randomized, double-blind, parallel-group, placebocontrolled study investigating the efficacy, safety and tolerability of 6 dosing groups of oral LOU064 in subjects with inadequately controlled CSU despite treatment with (second generation) H1-antihistamine. Study duration was 18 weeks (2 weeks of screening period; 12 weeks of treatment period and a 4 weeks follow-up period). Study had 7 arms: 10 mg LOU064 q.d.; 35 mg LOU064 q.d.; 100 mg LOU064 q.d.; 10 mg LOU064 b.i.d.; 25 mg LOU064 b.i.d.; 100 mg LOU064 b.i.d.; and Placebo Throughout study, subjects were treated with a 2nd generation H1-antihistamine at a locally approved licensed posology (background medication). Subjects could take an additional second generation H1-antihistamine that was eliminated primarily via renal excretion (e.g. cetirizine, levocetirizine or bilastine) as rescue medication. Eligible subjects could roll over to extension at Wk 12 or Wk 16
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LOU064 Arm 1<br>10 mg LOU064 qd capsule once daily | Drug: LOU064 Arm 1<br>* 10 mg LOU064 orally in the morning (once daily) and matching placebo in the evening from Day 1 to 85<br>|
| Experimental: LOU064 Arm 2<br>35 mg capsule qd LOU064 once daily | Drug: LOU064 Arm 2<br>* 35 mg of LOU064 orally in the morning (once daily) and matching placebo in the evening from Day 1 to 85<br>|
| Experimental: LOU064 Arm 3<br>100 mg capsule qd LOU064 once daily | Drug: LOU064 Arm 3<br>* 100 mg of LOU064 orally in the morning (once daily) and matching placebo in the evening from Day 1 to 85<br>|
| Experimental: LOU064 Arm 4<br>10 mg capsule LOU064 bid | Drug: LOU064 Arm 4<br>* 10mg bid of LOU064 orally, twice daily from Day 1 to 85<br>|
| Experimental: LOU064 Arm 5<br>25 mg capsule LOU064 bid | Drug: LOU064 Arm 5<br>* 25 mg bid of LOU064 orally, twice daily from Day 1 to 85<br>|
| Experimental: LOU064 Arm 6<br>100 mg capsule LOU064 bid | Drug: LOU064 Arm 6<br>* 100 mg bid of LOU064 orally, twice daily from Day 1 to 85<br>|
| Placebo Comparator: Placebo Arm<br>Participants took matching placebo twice daily | Drug: Placebo arm<br>* Matching placebo, orally, twice daily from Day 1 to 85<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 4 | UAS7 score change (LS mean Change) from baseline at Week 4 estimated with a mixed-effect repeated measurement analysis of UAS7 score change from baseline (FAS) The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates worse disease. A negative change score (week 4 score minus Baseline score) indicates improvement. | Baseline, Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weekly Urticaria Activity Score (UAS7) at Week 12 | UAS7 score change (LS mean Change) from baseline at Week 12 estimated with a mixed-effect repeated measurement analysis of UAS7 score change from baseline (FAS) | Week 12 | 
| Percentage of Participants With Either Complete Absence of Hives and Itch (UAS7=0) or Well-controlled Disease (UAS7<=6) | UAS7=0 and UAS7<=6 response rate over time by treatment group (non-responder imputation) The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates more severe disease. A negative change score (week 4 score minus Baseline score) indicates improvement. | Week 12 | 
| Cumulative Number of Weeks With an AAS7=0 Response | The Weekly angioedema activity score (AAS) is a validated tool to assess occurrence of episodes of angioedema. If the subject reports the occurrence of angioedema (opening question) with no, AAS score for this day is 0. If yes is the answer to the opening question, the subject will continue to answer questions about the duration, severity and impact on daily functioning and appearance of the angioedema. The AAS7 is a weekly AAS score (AAS7). Minimum and maximum possible AAS7 scores are 0-105. Higher score means more severe disease. | Baseline to Week 12 | 
| Percentage of Participants With DLQI Score of 0 or 1 | Percentage of subjects with DLQI 0/1 response by treatment group and visit (non-responder imputation) The Dermatology Life Quality Index (DLQI) is a 10-item dermatology-specific quality of life (QoL) measure. Subjects rate their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives thinking about the previous 7 days. An overall score is calculated and ranges from 0 to 30 (higher score meaning worse disease-related QoL). A DLQI score of 0 or 1 means that there is no impact of a skin disease on the patient's life. | Week 4 and Week 12 | 
| Mean Change From Baseline in DLQI Score | Summary of DLQI score and change from baseline The Dermatology Life Quality Index (DLQI) is a 10-item dermatology-specific quality of life (QoL) measure. Subjects rate their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives thinking about the previous 7 days. An overall score is calculated and ranges from 0 to 30 (higher score meaning worse disease-related QoL). | Baseline, Week 4 and Week 12 | 
| Area Under the Blood Concentration-time Curve (AUC) of LOU064 | Assessment of the area under the blood concentration-time curve (AUC) up to four hours following oral administration at Week 4 and Week 12 . | Week 4 and Week 12 | 
| Observed Maximum Blood Concentration (Cmax) of LOU064 | Assessment of the observed maximum blood concentration (Cmax) of LOU064 following drug administration at Week 4 and Week 12 . | Week 4 and Week 12 | 
| Time to Reach the Maximum Concentration (Tmax) of LOU064 | Assessment of the time to reach the maximum concentration (Tmax) of LOU064 following drug administration at Weeks 4 and 12 | Week 4 and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BTK inhibitor, Urticaria Activity Score, Angioedema Activity Score, CSU