臨床研究等提出・公開システム

The aim of this Phase 3 study is to investigate the use of benralizumab as a treatment for patients with EoE. The effect of doses of benralizumab on EoE histologic signs and symptoms will be assessed over a 52-week treatment period (including a 24-week double-blind placebo-controlled treatment period and a 28-week open-label treatment period). It is proposed that benralizumab will deplete eosinophils from GI tissue(s), improve the symptoms of dysphagia, and improve endoscopy scores as well as other markers of disease activity. Upon completion of the initial 52-week treatment period, patients will be offered an additional Open Label Extension period of at least 1 year, with benralizumab treatment and ongoing study assessments. (MESSINA)

A Multicenter, Randomized, Double-blind, Parallel-group, Placebo Controlled Study to Investigate the Use of Benralizumab for Eosinophilic Esophagitis

211

Patients were randomly assigned in a 1:1 ratio to receive either benralizumab 30 mg or placebo at 4-week intervals (DB period). The randomisation for adults was stratified by region (North America versus rest of world) and use of swallowed steroids at baseline (categorical, Yes/No). Adolescents were randomly assigned in a separate stratum with no other factors included. Patients with symptomatic and histologically active EoE before randomisation, male or female, and aged between 12 and 65 years (inclusive) were eligible for inclusion in this study. Approximately 170 patients were planned to be randomly assigned in a 1:1 ratio to benralizumab or matching placebo. This goal was exceeded as the recruitment period was extended to enrol the targeted number of adolescent patients as well as adult patients for the Early Time Point Sub-study. Overall, 211 patients were randomly assigned to study treatment and 210 received treatment during the DB period (103 received benralizumab and 107 received placebo). A total of 25 adult patients participated in the Early Time Point Sub-study (11 patients in the benralizumab group and 14 patients in the placebo group). The background of the patients enrolled in the DB period was as follows. - Mean age. Benralizumab: 33.9 years; placebo: 33.6 years -Gender Benralizumab: 31 (30.1%) women, 72 (69.9%) men; placebo: 22 (20.6%) women, 85 (79.4%) men -Race/Ethnicity Benralizumab: 6 Hispanic or Latino, 97 Non-Hispanic or Latino; placebo: 10 Hispanic or Latino, 94 Non-Hispanic or Latino

Of the 211 patients randomly assigned to study treatment, 206 patients (97.6%) completed DB treatment with study treatment, and 205 patients (97.2%) enrolled in the OL treatment period on study treatment and 1 patient (0.5%) enrolled in the OL period off study treatment. As of the primary analysis data cut-off date, 99 patients (46.9%) were ongoing in the OL period on study treatment, 98 patients (46.4%) completed OL treatment with study treatment, 8 patients (3.8%) discontinued OL treatment with study treatment, and 3 patients (1.4%) withdrew from the study during the OL period. Of the 89 patients who completed the OL period, 79 patients enrolled in the optional OLE period.

Treatment with benralizumab for up to 52 weeks in patients with EoE was well tolerated and displayed adverse event (AE) data that was consistent with the known safety profile of benralizumab, with no new safety findings. The safety profile of adolescents(< 18 years old) was consistent wik that of adults(18 years old or more). No patients had an AE with an outcome of death during the study. There were no AEs leading to discontinuation of IP during the DB period.

For the dual primary endpoints, treatment with benralizumab resulted in a statistically significant increase in the proportion of patients achieving histological response at Week 24 compared to placebo, but no statistically significant or clinically meaningful difference in the DSQ LS mean change from baseline was observed between benralizumab and placebo at Week 24. As statistical significance was not achieved on the DSQ endpoint (at the 5% level), other endpoints in the testing hierarchy could not be formally tested. The following efficacy conclusions were made in patients with symptomatic and histologically active EoE who were administered benralizumab 30 mg Q4W: [Dual-primary Endpoints] - Treatment with benralizumab significantly improved the proportion of patients who achieved histological response (. 6 eos/hpf) at Week 24 when compared with placebo (difference versus placebo: 80.8%, 95% CI: 72.9%, 88.8%; p < 0.0001). - The difference between treatment groups in LS mean change from baseline in DSQ score at Week 24 (3.0) was not statistically significant (95% CI: -1.36, 7.35; p = 0.1770). - Results of sensitivity analyses support the dual-primary endpoint conclusions. - Consistent results for the dual-primary endpoints were observed across all subgroups including the adolescent subgroup. [Key Secondary Endpoints] - Differences between treatment groups observed for percent change from baseline to Week 24 in tissue eosinophils, change from baseline to Week 24 in EoE-HSS total grade and total stage scores and proportion of treatment responders at Week 24 were considered nominally significant. - A greater LS mean percent reduction from baseline in tissue eosinophils (-94.8% versus 1.4% respectively) and greater LS mean reduction from baseline in EoE-HSS total grade and total stage score (-0.26 versus -0.09 and -0.20 versus -0.08, respectively) at Week 24 was observed in the benralizumab group compared with the placebo group, respectively. - The LS mean change from baseline in centrally-read EREFS total scores was similar between the benralizumab and placebo groups at Week 24 (-0.5 versus -0.4, respectively). - More patients in the benralizumab group were treatment responders at Week 24 (ie, achieved both histological response [. 6 eos/hpf] and clinically meaningful improvement in symptom response [. 30% improvement in DSQ score from baseline]) compared with the placebo group, driven by the histological response component. [Week 52 Efficacy (all available data from Weeks 24 to 52 up to the primary analysis data cut-off date)] - For histology-based endpoints, results of the dual-primary and key secondary endpoints were maintained up to Week 52 in patients randomised to benralizumab who continued into the OL period. - For endoscopic appearance (centrally-read EREFS total score) and symptom-based endpoints, no evidence of meaningful improvements with up to 52 weeks of benralizumab treatment were observed.

- Treatment with benralizumab 30 mg Q4W significantly improved histological response (<_ 6 eos/hpf) at Week 24 compared with placebo (87.4% versus 6.5% of patients, respectively; p < 0.0001) (dual-primary endpoint). - The mean change from baseline in DSQ scores was similar between the treatment groups over the 24-week DB period. The difference in LS mean change from baseline in DSQ score at Week 24 (3.0) was not statistically significant (95% CI: -1.36, 7.35; p = 0.1770) (dual-primary endpoint).

Feb. 02, 2024

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2061200026

Hibi Kazushige

Astrazeneca K.K.

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

RD-clinical-information-Japan@astrazeneca.com

Hibi Kaushige

Astrazeneca K.K.

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

+81-6-4802-3533

RD-clinical-information-Japan@astrazeneca.com

Complete

Sept. 22, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- Patients 12 to 65 years of age, inclusive, at the time of signing the informed consent or assent (if applicable) form.

- Documented previous diagnosis of EoE by endoscopy.

- Must be symptomatic at Visit 1 (screening) and Visit 2 (randomization)

1. A patient reported average of at least 2 days per week with an episode of dysphagia over the 4 weeks prior to the Visit 1 AND

2. An average of at least 2 days per week with an episode of dysphagia (Daily DSQ 2 or more) between Visit 1 and Visit 2, and at least 2 days per week with an episode of dysphagia (Daily DSQ 2 or more) in each of the 2 weeks immediately prior to randomization

- May be on background medications for EoE and related treatments during the study as long as the background medications have been stable for at least 4 weeks (8 weeks for PPI) prior to the screening. and there is agreement not to change type of background medication or dosage during the run-in period and for the first 52 weeks of the study unless a change is medically indicated.

- Negative serum pregnancy test for female patients of childbearing potential at Visit1.

- Women of childbearing potential must agree to use a highly effective form of birth control (confirmed by the Investigator) from randomization throughout the study duration and within 12 weeks after last dose if IP

- Other GI disorders such as active Helicobacter pylori infection, history of achalasia, esophageal varices, Crohn's disease, ulcerative colitis, inflammatory bowel disease, or celiac disease.

- Esophageal stricture that prevents the easy passage of a standard endoscope or any critical esophageal stricture that requires dilation during the run-in period.

- Esophageal dilation performed within 8 weeks prior to screening.

- Use of a feeding tube, or not eating solid food daily during the run-in period.

- Hypereosinophilic syndrome, defined by multiple organ involvement and persistent blood eosinophil count greater than1500 eos/ micro little.

- EGPA vasculitis.

- Eosinophilic gastritis, gastroenteritis, enteritis, or colitis documented by biopsy.

- Current malignancy, or history of malignancy with some specific exceptions.

- History of anaphylaxis to any biologic therapy or vaccine.

- Current active liver disease:

_Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen [HBsAg] or hepatitis C antibody), or other stable chronic liver disease are acceptable if patient otherwise meets eligibility criteria.

_Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level equal or greater than 3 times the upper limit of normal (ULN), confirmed by repeated testing during the run-in period.

- Helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent or assent (if applicable) is obtained that has not been treated with or has failed to respond to standard of care therapy.

- History of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
- Concomitant use of immunosuppressive medication.

- Initiation or change of a food-elimination diet regimen or reintroduction of a previously eliminated food group in the 6 weeks prior to start of the run-in period.

- Currently pregnant, breastfeeding, or lactating women.

Both

Eosinophilic Esophagitis

Biological: Benralizumab
Solution for injection in a single accessorized prefilled syringe (APFS) will be administered subcutaneously (SC), 1 mL fill volume.
Biological: Matching placebo
Matching placebo solution for injection in APFS, 1 mL fill volume. Placebo solution will be administered subcutaneously (SC), 1 mL fill volume

D3255C00001

Proportion of patients with a histologic response at Week 24, defined as a peak esophageal intraepithelial eosinophil count less or equal to 6 eos/hpf. The Dysphagia Symptom Questionnaire (DSQ) captures the presence and severity of dysphagia symptoms in the past day in a 4-item questionnaire. The DSQ score is calculated over 14-day periods and ranges from 0 to 84, with a lower score indicating less severe dysphagia.

+81-853-20-2515

Sept. 10, 2020

Canada/France/Germany/Israel/Italy/Netherlands/Poland/Russia/Spain/UK/US