Urticaria
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of GDC-0853 compared with placebo in participants with Refractory Chronic Spontaneous Urticaria (CSU) already treated with anti-histamines. Participants have the option to enter the Open-Label Extension (OLE) study after completing the 8-week treatment period.
Interventions
DRUGGDC-0853
GDC-0853 will be administered orally at dosages of 50, 150 and 200mg to participants, as per the dosing schedules described above.
DRUGPlacebo
Matching Placebo will be administered orally, as per the dosing schedules described above.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Aged 18-75 years, inclusive * Diagnosis of chronic spontaneous urticaria (CSU) refractory to H1 antihistamines at the time of randomization * Willing and able to complete an Urticaria Participant Daily eDiary for the duration of the study * No evidence of active or latent or inadequately treated infection with tuberculosis (TB) * Partcipants with a history of Bacille Calmette-Guérin (BCG) vaccination should be screened using the QuantiFERON-TB-Gold (QFT) test * Only for participants currently receiving proton-pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs): Treatment must be at a stable dose during the 2-week screening period prior to randomization and with a plan to remain at a stable dose for the duration of the study * For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least 4 weeks after the last dose of study drug. Women must refrain from donating eggs during this same period.
Exclusion criteria
* Treatment with omalizumab or other monoclonal antibody therapies used to treat CSU within 4 months prior to screening or primary nonresponse to omalizumab * Use of a non-biologic investigational drug or participation in an investigational study with a non-biologic drug within 30 days prior to study drug administration on Day 1 (or within 5 half-lives of the investigational product, whichever is greater) * Use of a biologic investigational therapy or participation in an investigational study involving biologic therapy within 90 days or 5 half-lives, whichever is greater, prior to study drug administration on Day 1 * Previous treatment with GDC-0853 or other Bruton's tyrosine kinase (BTK) inhibitors * Participants whose urticaria is solely due to physical urticaria * Other diseases with symptoms of urticaria or angioedema, including urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, lymphoma, or leukemia * Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, or other skin disease associated with itch such as psoriasis * Routine doses of the following medications within 30 days prior to screening: systemic or cutaneous (topical) corticosteroids (prescription or over the counter), hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide * Prior utilization of intravenous (IV) steroids for treatment of laryngeal angioedema * Intravenous immunoglobulin G (IV IG) or plasmapheresis within 30 days prior to screening * History of anaphylactic shock without clearly identifiable avoidable antigen * Hypersensitivity to GDC-0853 or any component of the formulation * Major surgery within 8 weeks prior to screening or surgery planned prior to end of study (12 weeks after randomization) * Require any prohibited concomitant medications * History of live attenuated vaccine within 6 weeks prior to randomization or requirement to receive these vaccinations at any time during study drug treatment * Evidence of clinically significant cardiac, neurologic, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic, or gastrointestinal (GI) disease that, in the investigator's opinion, would compromise the safety of the participant, interfere with the interpretation of the study results or otherwise preclude participant participation * Current treatment with astemizole, terfenadine, and/or ebastine * Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57 | Baseline and Day 57 | 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 (Day 57 score minus Baseline score) indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6) | Day 57 | 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. Participants with UAS7 score ≤6 are considered well controlled. |
| Change From Baseline in the UAS7 at Day 29 | Baseline and Day 29 | 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 (Day 29 score minus Baseline score) indicates improvement. |
| Percentage of Participants With Adverse Events (AEs) | Baseline up until 4 weeks after the last dose of study drug (up to 2 years, 5 months). | An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as Adverse Events. |
| Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Days 1, 8 and 57. | Plasma Concentration Data for fenebrutinib (GDC-0853) will be tabulated and summarised by visits. Descriptive summary statistics for Arithmetic Mean and Standard Deviation will be presented. Please note that the Placebo Cohorts were not evaluated for this Outcome Measure. |
Countries
Canada, Germany, United States
Participant flow
Recruitment details
The study was conducted at 21 centers in 3 countries.
Pre-assignment details
A total of 134 participants were enrolled at 21 centers.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Placebo Participants received matching placebo twice daily from Day 1 to 56. | 13 |
| Cohort 1: GDC-0853 200mg BID Participants received GDC-0853 200mg twice daily from Day 1 to 56. | 28 |
| Cohort 2: Placebo Participants received matching placebo up to twice daily from Day 1 to 56. | 23 |
| Cohort 2: GDC-0853 50mg QD Participants received GDC-0853 50mg once daily from Day 1 to 56. | 23 |
| Cohort 2: GDC-0853 150mg QD Participants received GDC-0853 150mg once daily from Day 1 to 56. | 24 |
| Cohort 2: GDC-0853 200mg BID Participants received GDC-0853 200mg twice daily from Day 1 to 56. | 23 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 | 1 | 1 | 0 | 1 |
| Overall Study | Data Entry Error | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 1 | 1 | 1 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 2 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 2: GDC-0853 200mg BID | Cohort 2: GDC-0853 150mg QD | Cohort 1: Placebo | Cohort 2: GDC-0853 50mg QD | Cohort 2: Placebo | Cohort 1: GDC-0853 200mg BID |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 42.8 Years STANDARD_DEVIATION 14.4 | 44.3 Years STANDARD_DEVIATION 13 | 43.3 Years STANDARD_DEVIATION 16.7 | 43.6 Years STANDARD_DEVIATION 11 | 45.0 Years STANDARD_DEVIATION 13.1 | 40.2 Years STANDARD_DEVIATION 14.7 | 41.3 Years STANDARD_DEVIATION 15.9 |
| Race/Ethnicity, Customized Asian | 15 Participants | 4 Participants | 1 Participants | 0 Participants | 3 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 15 Participants | 2 Participants | 5 Participants | 0 Participants | 2 Participants | 5 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiple | 3 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 116 Participants | 20 Participants | 19 Participants | 13 Participants | 21 Participants | 16 Participants | 27 Participants |
| Race/Ethnicity, Customized Not Stated | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 110 Participants | 16 Participants | 23 Participants | 10 Participants | 19 Participants | 18 Participants | 24 Participants |
| Sex: Female, Male Female | 104 Participants | 16 Participants | 20 Participants | 11 Participants | 18 Participants | 17 Participants | 22 Participants |
| Sex: Female, Male Male | 30 Participants | 7 Participants | 4 Participants | 2 Participants | 5 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 28 | 0 / 22 | 0 / 23 | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 8 / 13 | 16 / 28 | 7 / 22 | 7 / 23 | 13 / 24 | 12 / 24 |
| serious Total, serious adverse events | 0 / 13 | 3 / 28 | 0 / 22 | 0 / 23 | 0 / 24 | 0 / 24 |
Outcome results
Primary
Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57
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 (Day 57 score minus Baseline score) indicates improvement.
Time frame: Baseline and Day 57
Population: The Modified Intent-To-Treat (mITT) Population was defined as all participants who received at least one dose of study treatment grouped for analysis according to the treatment arm to which they were randomized. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Placebo | Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57 | -19.16 Score on a Scale | Standard Deviation 13.49 |
| Cohort 1: GDC-0853 200mg BID | Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57 | -24.05 Score on a Scale | Standard Deviation 9.74 |
| Cohort 2: Placebo | Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57 | -11.25 Score on a Scale | Standard Deviation 10.81 |
| Cohort 2: GDC-0853 50mg QD | Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57 | -15.69 Score on a Scale | Standard Deviation 14.25 |
| Cohort 2: GDC-0853 150mg QD | Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57 | -17.05 Score on a Scale | Standard Deviation 10.19 |
| Cohort 2: GDC-0853 200mg BID | Change From Baseline in the Urticaria Activity Score Over 7 Days (UAS7) at Day 57 | -21.80 Score on a Scale | Standard Deviation 14.8 |
p-value: 0.055990% CI: [-13.01, -1.03]Mixed Models Analysis
p-value: 0.889290% CI: [-6.6, 5.58]Mixed Models Analysis
p-value: 0.071790% CI: [-12.29, -0.57]Mixed Models Analysis
p-value: 0.009790% CI: [-15.5, -3.55]Mixed Models Analysis
Secondary
Change From Baseline in the UAS7 at Day 29
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 (Day 29 score minus Baseline score) indicates improvement.
Time frame: Baseline and Day 29
Population: The Modified Intent-To-Treat (mITT) Population was defined as all participants who received at least one dose of study treatment grouped for analysis according to the treatment arm to which they were randomized. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Placebo | Change From Baseline in the UAS7 at Day 29 | -9.69 Score on a Scale | Standard Deviation 10.7 |
| Cohort 1: GDC-0853 200mg BID | Change From Baseline in the UAS7 at Day 29 | -22.15 Score on a Scale | Standard Deviation 10.33 |
| Cohort 2: Placebo | Change From Baseline in the UAS7 at Day 29 | -9.05 Score on a Scale | Standard Deviation 9.82 |
| Cohort 2: GDC-0853 50mg QD | Change From Baseline in the UAS7 at Day 29 | -16.97 Score on a Scale | Standard Deviation 14.31 |
| Cohort 2: GDC-0853 150mg QD | Change From Baseline in the UAS7 at Day 29 | -13.75 Score on a Scale | Standard Deviation 12.93 |
| Cohort 2: GDC-0853 200mg BID | Change From Baseline in the UAS7 at Day 29 | -21.69 Score on a Scale | Standard Deviation 16.22 |
p-value: 0.00190% CI: [-18.94, -6.82]Mixed Models Analysis
p-value: 0.456590% CI: [-9.11, 3.46]Mixed Models Analysis
p-value: 0.171190% CI: [-11.1, 1.03]Mixed Models Analysis
p-value: 0.00590% CI: [-16.97, -4.56]Mixed Models Analysis
Secondary
Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6)
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. Participants with UAS7 score ≤6 are considered well controlled.
Time frame: Day 57
Population: The Modified Intent-To-Treat (mITT) Population was defined as all participants who received at least one dose of study treatment grouped for analysis according to the treatment arm to which they were randomized. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Placebo | Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6) | 30.8 Percentage of Participants |
| Cohort 1: GDC-0853 200mg BID | Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6) | 57.1 Percentage of Participants |
| Cohort 2: Placebo | Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6) | 21.7 Percentage of Participants |
| Cohort 2: GDC-0853 50mg QD | Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6) | 34.8 Percentage of Participants |
| Cohort 2: GDC-0853 150mg QD | Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6) | 45.8 Percentage of Participants |
| Cohort 2: GDC-0853 200mg BID | Percentage of Participants Who Are Well-Controlled (UAS7 ≤ 6) | 56.5 Percentage of Participants |
p-value: 0.1087Cochran-Mantel-Haenszel
p-value: 0.3418Cochran-Mantel-Haenszel
p-value: 0.0459Cochran-Mantel-Haenszel
p-value: 0.019Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Adverse Events (AEs)
An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as Adverse Events.
Time frame: Baseline up until 4 weeks after the last dose of study drug (up to 2 years, 5 months).
Population: The Safety-evaluable population was defined as all participants who received at least one dose of study drug with participants grouped according to their actual treatment. Due to a data entry error, one participant in the (Cohort 2: Placebo) arm was inadvertently analysed in the (Cohort 2: GDC-0853 200 mg BID) arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Placebo | Percentage of Participants With Adverse Events (AEs) | 61.5 Percentage of Participants |
| Cohort 1: GDC-0853 200mg BID | Percentage of Participants With Adverse Events (AEs) | 71.4 Percentage of Participants |
| Cohort 2: Placebo | Percentage of Participants With Adverse Events (AEs) | 54.5 Percentage of Participants |
| Cohort 2: GDC-0853 50mg QD | Percentage of Participants With Adverse Events (AEs) | 60.9 Percentage of Participants |
| Cohort 2: GDC-0853 150mg QD | Percentage of Participants With Adverse Events (AEs) | 66.7 Percentage of Participants |
| Cohort 2: GDC-0853 200mg BID | Percentage of Participants With Adverse Events (AEs) | 58.3 Percentage of Participants |
Secondary
Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints
Plasma Concentration Data for fenebrutinib (GDC-0853) will be tabulated and summarised by visits. Descriptive summary statistics for Arithmetic Mean and Standard Deviation will be presented. Please note that the Placebo Cohorts were not evaluated for this Outcome Measure.
Time frame: Days 1, 8 and 57.
Population: The PK-evaluable population was defined as all participants who received at least one dose of fenebrutinib (GDC-0853) and had at least 1 evaluable post-dose PK sample. Participants who received incorrect therapy different from the intended therapy were summarized in the group according to the therapy actually received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Placebo | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 1 | NA ng/mL | — |
| Cohort 1: Placebo | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 57 | 283 ng/mL | Standard Deviation 315 |
| Cohort 1: Placebo | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 8 | 378 ng/mL | Standard Deviation 389 |
| Cohort 1: GDC-0853 200mg BID | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 1 | NA ng/mL | — |
| Cohort 1: GDC-0853 200mg BID | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 57 | 19.6 ng/mL | Standard Deviation 26.3 |
| Cohort 1: GDC-0853 200mg BID | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 8 | 38.5 ng/mL | Standard Deviation 36.9 |
| Cohort 2: Placebo | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 8 | 178 ng/mL | Standard Deviation 237 |
| Cohort 2: Placebo | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 1 | NA ng/mL | — |
| Cohort 2: Placebo | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 57 | 24.7 ng/mL | Standard Deviation 17.7 |
| Cohort 2: GDC-0853 50mg QD | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 1 | NA ng/mL | — |
| Cohort 2: GDC-0853 50mg QD | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 57 | 219 ng/mL | Standard Deviation 293 |
| Cohort 2: GDC-0853 50mg QD | Plasma Concentrations of Fenebrutinib (GDC-0853) at Specified Timepoints | Day 8 | 424 ng/mL | Standard Deviation 385 |