Eosinophilic Chronic Rhinosinusitis, Nasal Polyposis
Conditions
Keywords
Benralizumab, Eosinophilic Chronic Rhinosinusitis with Nasal Polyps, Nasal Polyps, Asthma
Brief summary
This is a randomized, double-blind, placebo-controlled, parallel-group, international, multicenter, Phase 3 study to evaluate the efficacy and safety of repeat dosing of benralizumab 30 mg administered subcutaneously (SC) versus placebo in patients with severe nasal polyposis.
Detailed description
Approximately 250 patients will be randomized to receive benralizumab 30 mg SC or matching placebo. After enrolment, eligible patients will enter a 6-week screening/run in period. Patients who meet eligibility criteria will be randomised 1:1 at Week 0 (Day 0) to receive either placebo or benralizumab 30 mg SC every 4 weeks for the first 3 doses (Weeks 0, 4 and 8) and every 8 weeks thereafter (Weeks 16, 24, 32, 40 and 48). An end of treatment visit will be conducted at Week 56.All patients who complete the 56-week DB treatment period on investigational product (IP) may be eligible to continue into around one year OLE (Open Label Extension), during which all patients will receive 8 doses of benralizumab 30 mg. Patients in Benra arm during DB period will receive one dummy dose for the second dose during OLE (Open Label Extension). The last study visit will occur at 8 weeks after the last dose of IP (Week 112/FU). Patients who do not enter OLE (Open Label Extension), will have their last study visit at Week 56 (EoDB) for follow-up and without administration of IP.
Interventions
BIOLOGICALBenralizumab 30 mg
Benralizumab is 30 mg/ml solution for injection in accessorized pre-filled syringe, 1 ml fill volume. Benralizumab 30 mg subcutaneously will be injected every 4 weeks for the first 3 doses (Weeks 0, 4 and 8) and every 8 weeks thereafter (Weeks 16, 24, 32, 40 and 48). For OLE, Benralizumab 30 mg subcutaneously will be injected every 4 weeks for the first 3 doses and every 8 weeks for the rest 5 doses. For the patients on Benralizumab treatment during double blind period, placebo will be dosed at the second dose during OLE.
BIOLOGICALMatched placebo
Matching placebo solution for injection in accessorized pre-filled syringe. 1 ml fill volume. Matching placebo subcutaneously will be injected every 4 weeks for the first 3 doses (Weeks 0, 4 and 8) and every 8 weeks thereafter (Weeks 16, 24, 32, 40 and 48).
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Female or male patients aged 18 to 75 years inclusive 2. Stable Intranasal corticosteroids (INCS) use for at least 4 weeks prior to enrolment and throughout screening and DB period 3. History of treatment with systemic corticosteroids (SCS) or prior surgery for CRSwNP 4. Bilateral sinonasal polyposis with a nasal polyp score (NPS) of 5 at enrolment and randomization (unilateral score of at least 2 for each nostril) 5. Ongoing symptoms for at least 12 weeks prior to enrolment 6. Patient-reported moderate to severe nasal blockage score (NBS) ≥2 at enrolment 7. Bi-weekly mean NBS ≥ 1.5 at randomization 8. SNOT-22 total score ≥ 20 at enrolment and randomization 9. Documented physician-diagnosed asthma 10. Blood eosinophil count of \>2% or ≥150/μL at enrolment 11. LMS E≥M for Asian
Exclusion criteria
1. Any nasal and/or sinus surgery within 3 months prior to enrolment 2. Patients with conditions that makes them non evaluable for the co-primary efficacy endpoint including but not limited to: * Unilateral antrochoanal polyps * Nasal septal deviation that occludes at least one nostril * Current rhinitis medicamentosa * Allergic fungal rhinosinusitis or allergic fungal sinusitis; 3. Clinically important comorbidities (other eosinophil-driven diseases but CRSwNP) that may put the patient at risk, or may confound interpretation of clinical efficacy and/or safety results 4. Receipt of SCS for within 4 weeks prior to screening, or a scheduled SCS treatment during the study period. 5. Receipt of any marketed or investigational biologic product within 6 months of enrolment 6. Currently pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Endoscopic Total Nasal Polyp Score (NPS) at Week 56 | Baseline to Week 56 | The total nasal polyp score (NPS) is the sum of the right and left nostril scores (maximum of 8), as evaluated by nasal endoscopy. Higher scores indicate greater symptom severity. The left and right score will be based on a central read with a scale from 0 to 4. Each nasal endoscopy is evaluated by two independent physician reviewers. |
| Change From Baseline in Mean Nasal Blockage Score (NBS) at Week 56. | Baseline to week 56 | The NBS is an item in the NPSD. Patients were asked to rate the severity of their worst nasal blockage over the past 24 hours using the following response options: 0 - none; 1 - mild; 2 - moderate; 3 - severe. Higher scores indicate greater symptom severity. The NBS and the changes from baseline were summarised every two weeks (bi-weekly). Baseline was the average of daily responses from Day -13 to Day 1. Bi-weekly mean were calculated if at least 8 days in each 14-day period had evaluable data; otherwise, the biweekly mean was set to missing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Difficulty With Sense of Smell (DSS) Score at Week 56. | Baseline to Week 56 | The DSS is an item in the NPSD. Patients were asked to rate the severity of their worst difficulty with sense of smell over the past 24 hours using the following response options: 0-none; 1-mild; 2-moderate; 3-severe. Higher scores indicate greater symptom severity. The DSS and the changes from baseline were summarised every two weeks (bi-weekly). Baseline was the average of daily responses from Day -13 to Day 1. Bi-weekly mean of DSS was calculated if at least 8 days in each 14-day period have evaluable data; otherwise the bi-weekly mean was set to missing. |
| Sinus Opacification by CT Scan at Week 56. | Baseline to Week 56 | Change from baseline in Lund- Mackay score (LMS). The Lund-Mackay score scoring system is used to provide a quantitative assessment of nasal sinuses on sinus CT scans. Based on the sinus CT images, the five sinuses (maxillary, anterior ethmoid, posterior ethmoid, sphenoid and frontal) on each site are score by central radiologist as follows: (0-Normal; 1-Partial Opacification; 2-Total Opacification). The osteomeatal complex is scored for right and left sides (0 - Not occluded; 2- Occluded). The total score ranges from 0 to 24 (higher scores indicate poorer outcomes). |
| Disease Specific Health-related Quality of Life (HRQoL): Change From Baseline in SinoNasal Outcome Test (SNOT-22) Score at Week 56. | Baseline to Week 56 | SinoNasal Outcome Test 22 scores are participant-reported and assess physical problems, functional limitations and emotional consequences of SinoNasal conditions. Patient-reported symptom severity and symptom impact over the past 2 weeks are captured via a 6-point scale (0-No Problem to 5-Problem as bad as it can be). The total score is the sum of item scores and has a range from 0 to 110 (higher scores indicate poorer outcomes). |
| Time to First Nasal Polyp Surgery | Baseline to Week 56 | Time to the first surgery for CRSwNP= Start date of the first surgery for CRSwNP - date of randomisation + 1 |
| Time to First SCS Course for CRSwNP | Baseline to Week 56 | Time to the first SCS use for CRSwNP = Start date of the first SCS use for CRSwNP - date of randomisation + 1 |
| Time to First NP Surgery and/or SCS Use for CRSwNP | Baseline to Week 56 | Time to first surgery and/or SCS use for CRSwNP = earlier date of (start date of first surgery for CRSwNP, start date of first SCS use for CRSwNP) - date of randomisation + 1 |
| Change From Baseline in Bi-weekly Mean Nasal Polyps Symptom Diary Total Symptom Score at Week 56. | Baseline to Week 56 | The participant completed the nasal polyposis symptom diary each morning throughout the study. The participant was asked to consider their experience with nasal polyposis/nasal polyps over the past 24 hours when responding to each question. Participants were asked to report their experience with nasal polyposis symptoms (nasal blockage, nasal congestion, runny nose, postnasal drip (mucus drainage down the throat), headache, facial pain, facial pressure, difficulty with sense of smell). Participants reported the severity of each symptom and symptom impact at its worst using a 4-point verbal rating scale (0-None to 3-Severe). A total symptom score (range from 0 to 24) was calculated by taking the sum of the 8 equally weighted symptom items. Higher scores indicate greater symptom severity. |
| Percentage of Participants With Surgery and/or Use SCS for CRSwNP | Baseline to Week 56 | Nasal polyps surgery is defined as any procedure involving instruments resulting in incision and removal of tissue (e.g. polypectomy, endoscopic sinus surgery). An SCS course can be considered as a new course if the start date is preceded by at least 7 days after the end date of the last SCS course for CRSwNP (i.e. start date of the new course - end date of the last course \> 7) |
| Percentage of Participants With Surgery for CRSwNP | Baseline to Week 56 | Nasal polyps surgery is defined as any procedure involving instruments resulting in incision and removal of tissue (e.g. polypectomy, endoscopic sinus surgery). |
| Percentage of Participants With SCS Use for CRSwNP | Baseline to Week 56 | An SCS course can be considered as a new course if the start date is preceded by at least 7 days after the end date of the last SCS course for CRSwNP (i.e. start date of the new course - end date of the last course \> 7) |
Countries
Argentina, Australia, Belgium, Bulgaria, Chile, China, France, Hungary, Italy, Japan, Poland, Russia, Taiwan, Thailand, Turkey (Türkiye), United States, Vietnam
Contacts
PRINCIPAL_INVESTIGATORLuo Zhang, Prof. Dr.
Beijing Tongren Hospital
Participant flow
Recruitment details
A total of 723 participants were screened between 15NOV2019 and 01JUN2023. Of those, 295 were randomized to either the treatment (147 participants) or placebo (148 participants) arms of the double-blind treatment period. Eight participants were excluded due to Japan GCP breach. Therefore, 144 participants started in the treatment arm and 143 in the placebo arm, for a total of 287 participants.
Pre-assignment details
All patients completed a 6-week run-in period during which inclusion/exclusion criteria was assessed, medical history and surgical history were documented, Nasal endoscopy performed, and patient reported outcomes (PROs), clinical laboratories, and diet questionnaires were administered.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 33 Participants |
| Age, Categorical Between 18 and 65 years | 254 Participants |
| Age, Continuous | 49.5 Years STANDARD_DEVIATION 12.7 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 66 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized White | 73 Participants |
| Sex: Female, Male Female | 61 Participants |
| Sex: Female, Male Male | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 144 | 0 / 143 | 0 / 122 | 0 / 125 |
| other Total, other adverse events | 78 / 144 | 59 / 143 | 37 / 122 | 33 / 125 |
| serious Total, serious adverse events | 12 / 144 | 12 / 143 | 6 / 122 | 9 / 125 |
Outcome results
None listed