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A Study to Investigate Efficacy, Safety, and Tolerability of Remibrutinib Compared With Placebo in Adults With CINDU Inadequately Controlled by H1-antihistamines

Primary Purpose

Chronic Inducible Urticaria

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Remibrutinib
Placebo
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Inducible Urticaria focused on measuring CINDU, Chronic inducible urticaria, BTK, remibrutinib, symptomatic dermographsim, cold urticaria, cholinergic urticaria

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria for core period: Male and female participants ≥18 years of age at the time of signing of the ICFs Confirmed CINDU diagnosis (as per guidelines) for symptomatic dermographism, cold urticaria or cholinergic urticaria for ≥ 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 following response to the provocation test for each subtype is required at the randomization visit : Symptomatic Dermographism: A Total Fric Score of ≥3 using the FricTest® 4.0 and a numerical rating scale score of ≥5 for itch after the provocation test. Cold Urticaria: A Critical Threshold Temperature of ≥15°C using the TempTest® 4.0 and a numerical rating scale score of ≥5 for itch after the provocation test. Cholinergic Urticaria: A physician global assessment of severity of hives ≥ 2 using the Pulse-controlled ergometry test and a numerical rating scale score of ≥5 for itch after the provocation test. Cold Urticaria: Positive ice-cube test resulting in hives at the provocation site for participants at Screening. Cholinergic urticaria: Participants must show sweating in performing the pulse-controlled ergometry test on day of randomization. Participants with anhidrosis must not be included. Inclusion criteria for the OLE: Participants who have completed the Core period up to Week 52 and are willing to enter the OLE period Exclusion Criteria for core period: 1. Previous use of remibrutinib or other BTK inhibitors. Participants who have concomitant CSU at screening. Participants with resolved CSU at the time of screening can be included in the study. Participants who have a familial 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. Participants having a more defined other form of inducible urticaria than the target CINDU that is being considered for the participant's inclusion in this study. Diseases, other than chronic inducible urticaria, with urticaria or angioedema symptoms including but not limited to urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa) and hereditary or acquired angioedema 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 There are no exclusion criteria for OLE

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm 5

    Arm 6

    Arm Type

    Experimental

    Placebo Comparator

    Experimental

    Placebo Comparator

    Experimental

    Placebo Comparator

    Arm Label

    Remibrutinib, symptomatic dermographism group

    Placebo, symptomatic dermographism group

    Remibrutinib, cold urticaria group

    Placebo, cold urticaria group

    Remibrutinib, cholinergic urticaria group

    Placebo, cholinergic urticaria

    Arm Description

    Remibrutinib oral twice daily in participants with symptomatic dermographism

    Placebo oral twice daily, symptomatic dermographism

    Remibrutinib oral twice daily, cold urticaria

    Placebo oral twice daily, cold urticaria

    Remibrutinib oral twice daily, cholinergic urticaria

    Placebo oral twice daily, cholinergic urticaria

    Outcomes

    Primary Outcome Measures

    Proportion of participants with complete response in Total Fric Score; symptomatic dermographism
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Proportion of participants with complete response in critical temperature threshold; cold urticaria
    The Temptest is used to induce itch and hives in participants with cold urticaria. Critical temperature threshold (CTT), as measured by the Temptest, determines the highest temperature that induces symptoms.
    Proportion of participants with itch numerical rating scale =0; cholinergic urticaria
    Itch numerical rating scale, a scale from 0 to 10 Patients are asked to rate itching severity based on the worst level of itching in the past 24 h using an 11-point scale from 0 ("no itch") to 10 ("worst itch imaginable")

    Secondary Outcome Measures

    Change from baseline in Total Fric score; symptomatic dermographism
    Total Fric score, a scale from 0-4 where a positive response with all four pins is TFS=4, while a positive only 1 pin - the largest pin is TFS=1
    Change from baseline in criticial temperature threshold following Temptest; cold urticaria
    Critical temperature threshold, as measured by the Temptest, determines the highest temperature that induces symptoms
    Change from baseline in itch numerical rating scale; cholinergic urticaria
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    proportion of participants with Physician Global Assessment (PGA) severity of hives =0; cholinergic urticaria
    Physician global assessment of severity of hives. This assessment is scored 0 to 4 with 0=no hives, 1=mild hives, 2=moderate hives, 3=severe hives and 4=very severe hives
    Proportion of participants with complete response in TFS; symptomatic dermographism
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Proportion of participants with complete response in Critical Temperature threshold; cold urticaria
    Critical Temperature Threshold, as measured by the Temptest, is the highest temperature that induces symptoms
    Proportion of participants with complete response in itch numerical rating scale; cholinergic urticaria
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Change from baseline in itch numerical rating scale in participants with symptomatic dermographism
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Change from baseline in itch numerical rating scale in participants with cold urticaria
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Proportion of participants with complete response in Total Fric score; symptomatic dermographism
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Proportion of participants with complete response in Critical Temperature Threshold; cold urticaria
    Critical temperature threshold (CTT), as measured by the Temptest, determines the highest temperature that induces symptoms.
    Proportion of participants with itch NRS=0; cholinergic urticaria
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Change from baseline in TFS in participants with symptomatic dermographism
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Change from baseline in Critical Temperature Threshold in participants with cold urticaria
    Critical temperature threshold (CTT), as measured by the Temptest, determines the highest temperature that induces symptoms.
    Change from baseline in itch NRS in participants with cholinergic urticaria
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Change from baseline in itch NRS in participants with symptomatic dermographism
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Change from baseline in itch NRS in participants with cold urticaria
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Proportion of participants with cholinergic urticaria with PGA=0
    Physician global assessment of severity of hives is a 4-point scale (0 = no active disease, 1 = mild disease, 2 = moderate disease, 3 = severe disease).
    Change from baseline in weekly most bothersome symptom NRS score on the USDD
    Urtricara symptom daily diary (USDD). This daily diary records if the participant experiences any symptoms or avoided the triggers
    Proportion of participants with DLQI=0-1
    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.
    Occurrence of treatment emergent adverse events and serious adverse events during the study
    Treatment emergent adverse events and serious adverse events are those that occur at any time only after treatment has started

    Full Information

    First Posted
    July 28, 2023
    Last Updated
    September 18, 2023
    Sponsor
    Novartis Pharmaceuticals
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05976243
    Brief Title
    A Study to Investigate Efficacy, Safety, and Tolerability of Remibrutinib Compared With Placebo in Adults With CINDU Inadequately Controlled by H1-antihistamines
    Official Title
    A 52-week Multi-center, Randomized, Double-blind, Placebo Controlled, Basket Study With an Open-label Extension to Investigate the Efficacy, Safety, and Tolerability of Remibrutinib (LOU064) in Chronic Inducible Urticaria (CINDU) in Adults Inadequately Controlled by H1-antihistamines
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    December 19, 2023 (Anticipated)
    Primary Completion Date
    July 8, 2026 (Anticipated)
    Study Completion Date
    December 31, 2028 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Novartis Pharmaceuticals

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This is a Phase 3, parallel group, placebo-controlled, double-blind, confirmatory study in patients with CINDU, with an optional Open-label Extension (OLE). The purpose of the core period (52 weeks of treatment) of this study is to evaluate the efficacy, safety, and tolerability of remibrutinib (LOU064) vs. placebo in adults suffering from CINDU inadequately controlled by H1-antihistamines (H1-AHs). The purpose of the OLE period is to collect long-term efficacy, safety, and tolerability data on remibrutinib in participants after having completed the Core period
    Detailed Description
    This study consists of a core and extension periods. The Core period (6 arms) has a total duration of up to 60 weeks including a double-blind placebo-controlled treatment period until Week 24 followed by open-label treatment with remibrutinib up to Week 52. The primary endpoint for all CINDU subtypes is assessed at Week 12. The Core period consists of: Screening period (up to 4 weeks): During the screening period, participants who have provided informed consent will be assessed for study eligibility. Double-blind, placebo-controlled treatment period (24 weeks): 24 weeks of double-blind treatment with remibrutinib or placebo. Open-label treatment period (28 weeks): 28 weeks of open-label treatment with remibrutinib. Follow-up period: 4 weeks of treatment free follow-up. The open-label extension period consists of observation and treatment period. At the end of the core period of the study, if participants continue to experience symptoms, they will transition to the treatment period in OLE. If they do not experience symtpoms they will transition to the observation period in the OLE. The duration of the Open-label Extension period will be approximately 3 years where participants can switch from observation to treatment depending on if they start developing symptoms. Only those participants participating in the Open-label Extension Treatment period will receive remibrutinib. The participants in the Open-label Extension Observation period will not receive remibrutinib

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Chronic Inducible Urticaria
    Keywords
    CINDU, Chronic inducible urticaria, BTK, remibrutinib, symptomatic dermographsim, cold urticaria, cholinergic urticaria

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigatorOutcomes Assessor
    Masking Description
    This masking applies to the core period. There is no masking in the open-label extension (OLE).
    Allocation
    Randomized
    Enrollment
    348 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Remibrutinib, symptomatic dermographism group
    Arm Type
    Experimental
    Arm Description
    Remibrutinib oral twice daily in participants with symptomatic dermographism
    Arm Title
    Placebo, symptomatic dermographism group
    Arm Type
    Placebo Comparator
    Arm Description
    Placebo oral twice daily, symptomatic dermographism
    Arm Title
    Remibrutinib, cold urticaria group
    Arm Type
    Experimental
    Arm Description
    Remibrutinib oral twice daily, cold urticaria
    Arm Title
    Placebo, cold urticaria group
    Arm Type
    Placebo Comparator
    Arm Description
    Placebo oral twice daily, cold urticaria
    Arm Title
    Remibrutinib, cholinergic urticaria group
    Arm Type
    Experimental
    Arm Description
    Remibrutinib oral twice daily, cholinergic urticaria
    Arm Title
    Placebo, cholinergic urticaria
    Arm Type
    Placebo Comparator
    Arm Description
    Placebo oral twice daily, cholinergic urticaria
    Intervention Type
    Drug
    Intervention Name(s)
    Remibrutinib
    Intervention Description
    Remibrutinib treated groups and arms
    Intervention Type
    Other
    Intervention Name(s)
    Placebo
    Intervention Description
    Placebo treated groups and arms
    Primary Outcome Measure Information:
    Title
    Proportion of participants with complete response in Total Fric Score; symptomatic dermographism
    Description
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Time Frame
    Week 12
    Title
    Proportion of participants with complete response in critical temperature threshold; cold urticaria
    Description
    The Temptest is used to induce itch and hives in participants with cold urticaria. Critical temperature threshold (CTT), as measured by the Temptest, determines the highest temperature that induces symptoms.
    Time Frame
    Week 12
    Title
    Proportion of participants with itch numerical rating scale =0; cholinergic urticaria
    Description
    Itch numerical rating scale, a scale from 0 to 10 Patients are asked to rate itching severity based on the worst level of itching in the past 24 h using an 11-point scale from 0 ("no itch") to 10 ("worst itch imaginable")
    Time Frame
    Week 12
    Secondary Outcome Measure Information:
    Title
    Change from baseline in Total Fric score; symptomatic dermographism
    Description
    Total Fric score, a scale from 0-4 where a positive response with all four pins is TFS=4, while a positive only 1 pin - the largest pin is TFS=1
    Time Frame
    Week 12
    Title
    Change from baseline in criticial temperature threshold following Temptest; cold urticaria
    Description
    Critical temperature threshold, as measured by the Temptest, determines the highest temperature that induces symptoms
    Time Frame
    Week 12
    Title
    Change from baseline in itch numerical rating scale; cholinergic urticaria
    Description
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Time Frame
    Week 12
    Title
    proportion of participants with Physician Global Assessment (PGA) severity of hives =0; cholinergic urticaria
    Description
    Physician global assessment of severity of hives. This assessment is scored 0 to 4 with 0=no hives, 1=mild hives, 2=moderate hives, 3=severe hives and 4=very severe hives
    Time Frame
    Week 12
    Title
    Proportion of participants with complete response in TFS; symptomatic dermographism
    Description
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Time Frame
    Week 24
    Title
    Proportion of participants with complete response in Critical Temperature threshold; cold urticaria
    Description
    Critical Temperature Threshold, as measured by the Temptest, is the highest temperature that induces symptoms
    Time Frame
    Week 24
    Title
    Proportion of participants with complete response in itch numerical rating scale; cholinergic urticaria
    Description
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Time Frame
    Week 24
    Title
    Change from baseline in itch numerical rating scale in participants with symptomatic dermographism
    Description
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Time Frame
    Week 12
    Title
    Change from baseline in itch numerical rating scale in participants with cold urticaria
    Description
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Time Frame
    Week 12
    Title
    Proportion of participants with complete response in Total Fric score; symptomatic dermographism
    Description
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Time Frame
    Week 2
    Title
    Proportion of participants with complete response in Critical Temperature Threshold; cold urticaria
    Description
    Critical temperature threshold (CTT), as measured by the Temptest, determines the highest temperature that induces symptoms.
    Time Frame
    Week 2
    Title
    Proportion of participants with itch NRS=0; cholinergic urticaria
    Description
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Time Frame
    Week 2
    Title
    Change from baseline in TFS in participants with symptomatic dermographism
    Description
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Time Frame
    Week 2
    Title
    Change from baseline in Critical Temperature Threshold in participants with cold urticaria
    Description
    Critical temperature threshold (CTT), as measured by the Temptest, determines the highest temperature that induces symptoms.
    Time Frame
    Week 2
    Title
    Change from baseline in itch NRS in participants with cholinergic urticaria
    Description
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Time Frame
    Week 2
    Title
    Change from baseline in itch NRS in participants with symptomatic dermographism
    Description
    Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)
    Time Frame
    Week 2
    Title
    Change from baseline in itch NRS in participants with cold urticaria
    Description
    Itch numerical rating scale (NRS), scale from 0 to 10. 0 ("no itch") to 10 ("worst imaginable itch").
    Time Frame
    Week 2
    Title
    Proportion of participants with cholinergic urticaria with PGA=0
    Description
    Physician global assessment of severity of hives is a 4-point scale (0 = no active disease, 1 = mild disease, 2 = moderate disease, 3 = severe disease).
    Time Frame
    Week 2
    Title
    Change from baseline in weekly most bothersome symptom NRS score on the USDD
    Description
    Urtricara symptom daily diary (USDD). This daily diary records if the participant experiences any symptoms or avoided the triggers
    Time Frame
    Week 12
    Title
    Proportion of participants with DLQI=0-1
    Description
    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.
    Time Frame
    Week 12
    Title
    Occurrence of treatment emergent adverse events and serious adverse events during the study
    Description
    Treatment emergent adverse events and serious adverse events are those that occur at any time only after treatment has started
    Time Frame
    Week 52

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria for core period: Male and female participants ≥18 years of age at the time of signing of the ICFs Confirmed CINDU diagnosis (as per guidelines) for symptomatic dermographism, cold urticaria or cholinergic urticaria for ≥ 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 following response to the provocation test for each subtype is required at the randomization visit : Symptomatic Dermographism: A Total Fric Score of ≥3 using the FricTest® 4.0 and a numerical rating scale score of ≥5 for itch after the provocation test. Cold Urticaria: A Critical Threshold Temperature of ≥15°C using the TempTest® 4.0 and a numerical rating scale score of ≥5 for itch after the provocation test. Cholinergic Urticaria: A physician global assessment of severity of hives ≥ 2 using the Pulse-controlled ergometry test and a numerical rating scale score of ≥5 for itch after the provocation test. Cold Urticaria: Positive ice-cube test resulting in hives at the provocation site for participants at Screening. Cholinergic urticaria: Participants must show sweating in performing the pulse-controlled ergometry test on day of randomization. Participants with anhidrosis must not be included. Inclusion criteria for the OLE: Participants who have completed the Core period up to Week 52 and are willing to enter the OLE period Exclusion Criteria for core period: 1. Previous use of remibrutinib or other BTK inhibitors. Participants who have concomitant CSU at screening. Participants with resolved CSU at the time of screening can be included in the study. Participants who have a familial 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. Participants having a more defined other form of inducible urticaria than the target CINDU that is being considered for the participant's inclusion in this study. Diseases, other than chronic inducible urticaria, with urticaria or angioedema symptoms including but not limited to urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa) and hereditary or acquired angioedema 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 There are no exclusion criteria for OLE
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Novartis Pharmaceuticals
    Phone
    1-888-669-6682
    Email
    novartis.email@novartis.com
    First Name & Middle Initial & Last Name or Official Title & Degree
    Novartis Pharmaceuticals
    Phone
    +41613241111
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Novartis Pharmaceuticals
    Organizational Affiliation
    Novartis Pharmaceuticals
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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    A Study to Investigate Efficacy, Safety, and Tolerability of Remibrutinib Compared With Placebo in Adults With CINDU Inadequately Controlled by H1-antihistamines

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