臨床研究等提出・公開システム

A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-Ranging, Phase 2b Study to Evaluate Efficacy and Safety of Tezepelumab for the Treatment of Chronic Spontaneous Urticaria

Study to Evaluate Tezepelumab in Adults With Chronic Spontaneous Urticaria

183

Sex: 134 women (73.2 %) and 49 men (26.8 %). Age: mean (SD) = 42.9 (14.5) years. Race: 114 White (62.3 %), 60 Asian (32.8 %), 7 Black (3.8 %), 1 Multiple (0.5 %), 1 other (0.5 %). Ethnicity: 169 Not Hispanic/Latino (92.3 %), 14 Hispanic/Latino (7.7 %).

183 subjects were enrolled and randomized to treatment groups: placebo (48 subjects), omalizumab (31 subjects), tezepelumab 210 mg (52 subjects), and tezepelumab 420 mg (52 subjects). A total of 165 subjects (90.2%) completed the study. Eighteen subjects (9.8%) discontinued the study: withdrawal of consent from study (9 [4.9%]), lost to follow-up (5 [2.7%]), protocol-specified criteria (3 [1.6%]), and decision by sponsor (1 [0.5%]).

The subject incidence of treatment-emergent adverse events (hereafter referred to as adverse events) in the placebo, omalizumab, tezepelumab 210 mg, and tezepelumab 420 mg was 23 (47.9 %), 24 (77.4 %), 29 (55.8 %), and 28 (53.8 %), respectively. The subject incidence of adverse events was highest in omalizumab group. Adverse events by preferred term (PT) reported for >= 10 % of subjects in any treatment group were as follows: - COVID-19: 3 (6.3 %), 2 (6.5 %), 8 (15.4 %), and 5 (9.6 %) - Headache: 2 (4.2 %), 1 (3.2 %), 5 (9.6 %), and 6 (11.5 %) No subjects had fatal adverse events during the study. One subject (3.2%) in the omalizumab group (2 events of intentional self-injury) and 1 subject (1.9%) in the tezepelumab 210 mg group (1 event of acute lymphocytic leukemia) had serious adverse events.

1. Primary Outcome The improvement in UAS7 from baseline in both the tezepelumab groups was not statistically significant compared with placebo at week 16, whereas the improvement in both tezepelumab groups was numerically higher than placebo at week 32. The (least squares mean [LSM] [SE] of change from baseline) (tezepelumab 210 mg and 420 mg, and placebo, respectively) were as follows: - week 16: (-13.5 [1.6], -14.7 [1.5], -13.6 [1.6]) 2. Secondary Outcome In the overall population, numerical improvement from baseline in most secondary efficacy endpoints was observed in both tezepelumab groups at week 16, but there was no statistically significant difference from placebo. In addition to the secondary endpoints, the additional important finding at the time of the final analysis in the study was that tezepelumab groups continued to show improvement in the continuous secondary efficacy endpoints and most of the binary secondary efficacy endpoints until the EOS at week 32 without treatment (tezepelumab was administered up to week 16). The sustained treatment effect with tezepelumab at week 32 was observed for both tezepelumab doses.

- The improvement in UAS7 from baseline in both the tezepelumab groups was not statistically significant compared with placebo at week 16 in the overall (p > 0.05). - The incidence of all adverse events was higher in omalizumab group compared with the tezepelumab groups and the placebo group for the overall population. The incidence of SAEs, those leading to discontinuation of investigational product, severe adverse events, and EOIs was generally similar between the treatment groups.

Yes

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210170

Kimura Takeshi

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

clinicaltrials_japan@amgen.com

Contact Local

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

+81-80-7217-8592

clinicaltrials_japan@amgen.com

Complete

April. 15, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Signed informed consent must be obtained prior to participation in the study.
2. Male and female participants >= 18 years and <= 80 years of age at the time of screening.
3. Chronic spontaneous urticaria (CSU) diagnosis for >= 6 months at the time of screening.
4. CSU inadequately controlled by second generation H1-antihistamines (sgAH) at enrollment, as defined by all of the following:
-The presence of itch and hives for >= 6 consecutive weeks at any time prior to screening visit 2.
- Failure to respond to an sgAH (up to 4 times the approved dose)
- Urticaria Activity Score over 7 days (UAS7) (range 0-42) >= 16 and Hives Severity Score over 7 days (HSS7) (range 0-21) >= 8 during the 7 days prior to enrollment.
5. Participant with CSU who discontinued, is intolerant to, or was an inadequate responder to anti-IgE therapies despite being treated with omalizumab 300 mg every 4 weeks (Q4W) for 6 months or higher doses of omalizumab > 2 months or another anti-IgE therapy. Note: This criterion is only applicable for anti-IgE- experienced participants.
6. Participant willing and able to complete a daily symptom eDiary for the duration of the study and adhere to the study visit schedules.
7. Subject must have been on a sgAH at approved or increased doses (up to 4x the approved dose) for treatment of CSU for at least 3 consecutive days immediately prior to the day -14 screening visit (screening visit 2) and must have documented current use on the day of screening visit 1.

Disease related, including but not limited to:
1. Urticaria is solely due to inducible urticaria
2. Active dermatologic diseases (or conditions) other than chronic urticaria, with urticaria wheals or angioedema symptoms such as urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa) and hereditary or acquired angioedema (eg, due to C1 inhibitor deficiency)
3. Any other active skin disease associated with chronic itching that might influence, in the investigator's opinion, the study evaluations and results (eg, atopic dermatitis, dermatitis herpetiformis, senile pruritus, etc.)
4. History of a clinically significant infection within 28 days prior to day 1 that, in the opinion of the investigator or medical monitor, might compromise the safety of the participant in the study, interfere with evaluation of the investigational product, or reduce the participants ability to participate in the study.
5 .Evidence of active tuberculosis (TB) (in the opinion of the investigator), either treated or untreated, or a positive purified protein derivative (PPD) or QuantiFERON-TB Gold Plus (QFT-Plus) test for TB during screening.
6 .History of malignancy, except for basal cell carcinoma or in situ carcinoma of the cervix treated with apparent success with curative therapy >= 12 months prior to screening or other malignancies treated with apparent success with curative therapy >= 5 years prior to screening visit 1.
7 .Subject is unable to complete an electronic patient diary or complete questionnaires, or does not meet the required level of compliance with the eDiary during the 14 days sgAH stabilization period.

Other medical conditions
8 .History or evidence of severe depression, schizophrenia, previous suicide attempts, or suicidal ideation.

Prior/concomitant therapy, including but not limited to:
9 .Treatment with any biologic products (eg, omalizumab, ligelizumab) within 4 months or 5 half-lives (whichever is longer) prior to screening visit 1.
10 .Routine (daily or every other day for 5 or more consecutive days) use of systemic corticosteroids, systemic hydroxychloroquine, methotrexate, cyclosporine A, cyclophosphamide, tacrolimus, azathioprine, and mycophenolate mofetil within 30 days prior to screening visit 1.
11 .Major surgery within 8 weeks prior to screening visit 1 or planned inpatient surgery or hospitalization during the study period.
12 .Receipt of Ig or blood products within 30 days prior to screening visit 1.
13 .Vaccination with a live or attenuated vaccine within 30 days prior to screening visit 1. Receipt of COVID-19 vaccines and inactive/killed vaccinations (eg, inactive influenza) are allowed, provided the vaccinations are not administered within 7 days before or after any study dosing visit.
14 .Known hypersensitivity, including severe hypersensitivity reactions and/or history of anaphylactic shock, to any of the products or components to be administered during dosing or to products of similar chemical classes (ie, to murine, chimeric, or human antibodies.

Both

Chronic Spontaneous Urticaria

- Biological: Tezepelumab Dose 1
Subcutaneous injection. Q2W.
- Biological: Tezepelumab Dose 2
Subcutaneous injection. Q4W.
- Biological: Omalizumab
Subcutaneous injection.
Other Name: Xolair
- Biological: Placebo
Subcutaneous injection.

Change from Baseline in Urticaria Activity Score over 7 days (UAS7) at Week 16 [ Time Frame: Baseline and Week 16 ]
The UAS is a CSU-specific patient-reported outcome measure with 2 components: Hives Severity Score (HSS) for number of wheals and an Itch Severity Score (ISS) for itch intensity, and are each scored from 0 (no wheals, no itch) to 3 (>50 wheals, severe itch) for the previous 24 hours. The HSS and ISS are combined to give a daily UAS ranging from 0 to 6. The sum of the daily UAS over a 7-day period provides the UAS7, from 0 (no symptoms) to 42 (severe urticaria). The least squares mean (LSM) estimates are based on the repeated measure model with stratification factor (prior anti-IgE status), baseline UAS7, treatment, study week and the interaction between treatment and study week. A negative change from baseline indicates an improvement in urticaria activity.

1. Change From Baseline in ISS Over 7 Days (ISS7) at Week 16 [Time Frame: Baseline and Week 16]
2. Change From Baseline in HSS Over 7 Days (HSS7) at Week 16 [Time Frame: Baseline and Week 16]
3. Number of Participants With a UAS7 of <= 6 (Minimal Residual Disease) at Week 16 [Time Frame: Week 16]
4. Number of Participants With a Change From Baseline in UAS7 of <= -10 (Minimal Important Difference) [Time Frame: Baseline and Week 16]
5. Number of Participants With a UAS7 = 0 at Week 16 (Complete Response) [Time Frame: Week 16]
6. Number of Participants With ISS7 = 0 at Week 16 (Complete Resolution) [Time Frame: Week 16]
7. Number of Participants With a Change From Baseline in ISS7 of <= -5 (Minimal Important Difference) [Time Frame: Baseline and Week 16]
8. Number of Participants With HSS7 = 0 at Week 16 (Complete Resolution) [Time Frame: Week 16]
9. Number of Participants With a Change From Baseline in HSS7 of <= -5.5 (Minimal Important Difference) [Time Frame: Baseline and Week 16]
10. Change From Baseline in Weekly Sleep Interference Score (SIS7) at Week 16 [Time Frame: Baseline and Week 16]
11. Change From Baseline in Weekly Sleep Quality Score (SQS7): Sum of Daily SQS at Week 16 [Time Frame: Baseline and Week 16]
12. Change From Baseline in SQS7: Sum of Average Daily Q1 - Q3 at Week 16 [Time Frame: Baseline and Week 16]
13. Change From Baseline in Urticaria Control Test (UCT) Score at Week 16 [Time Frame: Baseline and Week 16]
14. Change From Baseline in Weekly Angioedema Activity Score (AAS7) at Week 16 [Time Frame: Baseline and Week 16]
15. Number of Cumulative Weeks That Participants Achieved AAS7 = 0 at Week 16 (Angioedema Occurrence Free) [Time Frame: Baseline to Week 16]
16. Change From Baseline in the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) at Week 16 [Time Frame: Baseline and Week 16]
17. Change From Baseline in the Dermatology Life Quality Index (DLQI) at Week 16 [Time Frame: Baseline and Week 16]
18. Change From Baseline in the Angioedema Quality of Life Questionnaire (AE-QoL) at Week 16 [Time Frame: Baseline and Week 16]
19. Change From Baseline in the Angioedema Control Test (AECT) Score at Week 16 [Time Frame: Baseline and Week 16]
20. Number of Participants With an AECT Score = 16 at Week 16 (Complete Control) [Time Frame: Baseline and Week 16]
21. Change From Baseline in the Work Productivity and Activity Impairment Questionnaire: Chronic Urticaria (WPAI-CU) Score at Week 16 [Time Frame: Baseline and Week 16]
22. Number of Cumulative Days of sgAH Rescue Medication Use From Baseline to Week 16 [Time Frame: Baseline to Week 16]
23. Serum Concentration of Tezepelumab [Time Frame: Week 1 pre-dose, Weeks 2, 4, 8, 12, 16, 24, and 32]
24. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [Time Frame: Day 1 Week 1 to Week 32, up to 32 weeks]

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Jan. 21, 2021

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