Chronic Rhinosinusitis With Nasal Polyps
Conditions
Keywords
Chronic rhinosinusitis with nasal polyps, Nasal polyps, Nasal polyposis
Brief summary
A Multicentre, Randomised, Double-Blind, Parallel-Group, Placebo-Controlled Phase 3 Efficacy and Safety Study of Tezepelumab in Participants with Severe Chronic Rhinosinusitis with Nasal Polyposis
Detailed description
This is a multicentre, randomised, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and safety of tezepelumab in adults with severe, chronic rhinosinusitis with nasal polyposis. Approximately 400 subjects will be randomized globally. Participants will receive tezepelumab, or placebo, administered via subcutaneous injection using the accessorized pre-filled syringe (APFS) every 4 weeks, over a 52-week treatment period. The study also includes a post-treatment follow-up period of 12-24 weeks for participants who complete the 52-week treatment period. All participants will have background mometasone furoate nasal spray or equivalent intranasal corticosteroid at a stable dose from Visit 1 and throughout the screening and study period.
Interventions
BIOLOGICALExperimental: Tezepelumab
Tezepelumab subcutaneous injection
OTHERPlacebo
Placebo subcutaneous injection
DRUGMometasone furoate or equivalent intranasal corticosteroid
Background MFNS or equivalent INCS at stable dose
Sponsors
AstraZeneca
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-Blind
Intervention model description
Subjects will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneously.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants with physician-diagnosed CRSwNP for at least 12 months prior to Visit 1 that have: 1. Severity consistent with need for surgery as defined by total NPS ≥ 5 (≥ 2 for each nostril) at screening, as determined by the central reader 2. Nasal Congestion Score (NCS) ≥ 2 at Visit 1 3. Ongoing documented NP symptoms over \> 8 weeks prior to screening such as rhinorrhea and/or reduction/loss of smell 2. SNOT-22 total score ≥ 30 at screening (Visit 1) 3. Any standard of care for treatment of CRSwNP provided the participant is stable on that treatment for 30 days prior to Visit 1 4. Documented treatment of nasal polyposis exacerbation with SCS for at least 3 consecutive days or one IM depo-injectable dose (or contraindications/intolerance to) within the past 12 months prior to Visit 1 but not within the last 3 months prior to Visit 1 and/or any history of NP surgery (or contraindications/intolerance to)
Exclusion criteria
1. Any clinically important comorbidities other than asthma (e.g. active lung infection, bronchiectasis, pulmonary fibrosis, cystic fibrosis, primary ciliary dyskinesia, allergic bronchopulmonary mycosis, hypereosinophilic syndromes, etc.) that could confound interpretation of clinical efficacy results. 2. Sinus surgery within 6 months of screening visit OR any sinus surgery in the past which changed the lateral wall of the nose making NPS evaluation impossible. 3. Positive COVID-19 PCR test (or COVID-19 rapid test) or COVID-19 entry screening questionnaire during the screening visit. Evaluation will be based on on local standard of care as determined by current local guidelines. 4. Regular use of decongestants (topical or systematic) at enrolment is not allowed unless used for endoscopic procedure 5. Use of immunosuppressive medication (including but not limited to: methotrexate, troleandomycin, cyclosporine, azathioprine, mycophenolate, tacrolimus, gold, penicillamine, sulfasalazine, hydroxychloroquine, systemic corticosteroids or any experimental anti-inflammatory therapy) within 3 months prior to Visit 1 and during the study period. Systemic corticosteroid use is defined as treatment with a burst of systemic corticosteroids for at least 3 consecutive days or a single IM depo-injectable dose of corticosteroids (considered equivalent to a 3-day burst of systemic corticosteroids). 6. Receipt of COVID-19 vaccine (regardless of vaccine delivery platform) 28 days prior to date of IP administration at Visit 3 (randomisation visit).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Nasal Polyp Score at Week 52 | Baseline to Week 52 | 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 Bi-weekly Mean Nasal Congestion Score (NCS) at Week 52 | Baseline to Week 52 | The NCS is captured by one item in the NPSD (nasal polyps symptom diary) asking participants to rate the severity of their worst NC over the past 24 hours using the following response options: 0 - None; 1 - Mild; 2 - Moderate; 3 - Severe. Baseline will be the mean of daily responses from Day -13 to Day 0. Bi-weekly (14-day) mean NCS will be calculated if at least 8 days in each 14-day period has evaluable data; otherwise the bi-weekly mean is set to missing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Bi-weekly Mean Loss of Smell at Week 52 | Baseline to Week 52 | Participant reported sense of smell will be evaluated as part of the NPSD. Loss of smell is captured by the DSS item (difficulty with sense of smell) in the NPSD asking participants 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. Baseline will be the mean of daily responses to the from Day -13 to Day 0. Bi-weekly (14-day) mean loss of smell will be calculated if at least 8 days in each 14-day period has evaluable data; otherwise the bi-weekly mean is set to missing. |
| Change From Baseline in SinoNasal Outcome Test 22 (SNOT-22) at Week 52 | Baseline to Week 52 | 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). |
| Change From Baseline in Lund Mackay Score Evaluated by CT at Week 52. | Week 52 | 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). |
| Percentage of Participants With Nasal Polyp Surgery Decision and/or Systemic Corticosteroid for Nasal Polyposis up to Week 52 | Up to Week 52 | Surgery is defined as any procedure involving instruments resulting in incision and removal of tissue (e.g., polypectomy, endoscopic sinus surgery). Rescue treatment of NP is defined as requiring treatment with systemic corticosteroids (SCS) for at least 3 consecutive days (a single depo-injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids). Time to first NP surgery decision or SCS for NP = (date of the first NP surgery decision or start date of first SCS for NP use - date of randomisation)+1. Kaplan Meier estimates of percentage of participants with events and 95% confidence interval are provided for each treatment group. |
| Percentage of Participants With Nasal Polyp Surgery Decision up to Week 52 | Up to Week 52 | Surgery is defined as any procedure involving instruments resulting in incision and removal of tissue (e.g., polypectomy, endoscopic sinus surgery). Time to first NP surgery decision = (date of the first NP surgery decision - date of randomisation)+1. Kaplan Meier estimates of percentage of participants with events and 95% confidence interval are provided for each treatment group. |
| Percentage of Participants With Systemic Corticosteroids for Nasal Polyposis up to Week 52 | Up to Week 52 | Systemic corticosteroids (SCS) for nasal polyposis (NP) is defined as requiring at least 3 consecutive days (a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of SCS) for NP. Time to first SCS for NP = (start date of first SCS for NP use - date of randomisation)+1. Kaplan Meier estimates of percentage of participants with events and 95% confidence interval are provided for each treatment group. |
| Change From Baseline in Bi-weekly Mean Nasal Polyposis Symptom Diary Total Symptom Score at Week 52 | Baseline to Week 52 | 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. |
| Change From Baseline in Pre-bronchodilator Forced Expiratory Volume (L) in 1 Second at Week 52. | Baseline to Week 52 | For participants with comorbid asthma and aspirin exacerbated respiratory disease (AERD)/nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NSAID-ERD), difference in change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) in the tezepelumab arm as compared to placebo at Week 52. FEV1 is defined as the volume of air exhaled from the lungs in the first second of forced expiration. |
Countries
Canada, China, Denmark, Germany, Hungary, Japan, Poland, Spain, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORBrian Lipworth, MD
University of Dundee
PRINCIPAL_INVESTIGATORJoseph K Han, MD
Eastern Virginia Medical School
Participant flow
Recruitment details
A total of 416 participants were randomized, 6 of which were removed from analyses due to GCP issues, before study unblinding. The remaining 410 were randomized to either the treatment arm (204 participants) or placebo (206 participants) arms of the double-blind treatment period. Two participants were randomized but not dosed (one was withdrawal by subject, one did not meet inclusion/exclusion criteria). Therefore, 203 participants started in the treatment arm and 205 in the placebo arm.
Pre-assignment details
All patients completed a 5-week run-in period during which inclusion/exclusion criteria were assessed, medical history was recorded, nasal endoscopy and biopsy and CT scan were performed, and patient-reported outcomes (PROs) and clinical laboratory tests were performed.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 26 Participants |
| Age, Categorical Between 18 and 65 years | 179 Participants |
| Age, Continuous | 49.7 years STANDARD_DEVIATION 13.63 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 194 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 97 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants |
| Race/Ethnicity, Customized Other | 6 Participants |
| Race/Ethnicity, Customized White | 149 Participants |
| Sex: Female, Male Female | 77 Participants |
| Sex: Female, Male Male | 266 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 408 | 0 / 203 | 1 / 205 |
| other Total, other adverse events | 20 / 408 | 119 / 203 | 119 / 205 |
| serious Total, serious adverse events | 0 / 408 | 11 / 203 | 14 / 205 |
Outcome results
None listed