Efficacy and Safety of Tezepelumab in Participants With Severe Chronic Rhinosinusitis With Nasal Polyposis

Study Overview
=================
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. Subjects will receive tezepelumab, or placebo, administered via subcutaneous injection using the accessorized pre-filled syringe (APFS), 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.

Official Title
-----------------
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 (WAYPOINT)

Conditions
-----------------
Chronic Rhinosinusitis With Nasal Polyps

Intervention / Treatment
-----------------
* Biological: Experimental: Tezepelumab
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants with physician-diagnosed CRSwNP for at least 12 months prior to Visit 1 that have: Severity consistent with need for surgery as defined by total NPS ≥ 5 (≥ 2 for each nostril) at screening, as determined by the central reader Nasal Congestion Score (NCS) ≥ 2 at Visit 1 Ongoing documented NP symptoms over > 8 weeks prior to screening such as rhinorrhea and/or reduction/loss of smell SNOT-22 total score ≥ 30 at screening (Visit 1) Any standard of care for treatment of CRSwNP provided the participant is stable on that treatment for 30 days prior to Visit 1 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: 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. 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. 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. Regular use of decongestants (topical or systematic) at enrolment is not allowed unless used for endoscopic procedure 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). Receipt of COVID-19 vaccine (regardless of vaccine delivery platform) 28 days prior to date of IP administration at Visit 3 (randomisation visit).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneously.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tezepelumab<br>Tezepelumab subcutaneous injection, in an accessorized pre-filled syringe. | Biological: Experimental: Tezepelumab<br>* Tezepelumab subcutaneous injection<br>* Other names: Tezepelumab;|
| Placebo Comparator: Placebo<br>Placebo subcutaneous injection, in an accessorized pre-filled syringe. | Other: Placebo<br>* Placebo subcutaneous injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nasal Polyp Score | Change from baseline in total Nasal Polyp Score at Week 52. The Nasal Polyp Score is the sum of the right and left nostril scores (maximum 8), as evaluated by nasal endoscopy. | Baseline to Week 52 | 
| Participant Reported Nasal Congestion | Change from baseline in bi-weekly mean Nasal Congestion score evaluated as part of the Nasal Polyposis Symptom Diary at Week 52. Nasal Congestion Score is captured by asking participants to rate the severity of their worst nasal congestion over the past 24 hours (0-None; 1-Mild; 2-Moderate; 3-Severe). | Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Loss of Smell | Change from baseline in bi-weekly mean loss of smell evaluated by the Nasal Polyposis Symptom Diary by asking patients to rate the severity of their worst difficulty with sense of smell over the past 24 hours at week 52. Response options include: 0- None; 1- Mild; 2- Moderate; 3- Severe. | Baseline to Week 52 | 
| Nasal Polyp-Quality of Life Compared with Placebo | Change from baseline in SinoNasal Outcome Test 22 (SNOT-22) scores at 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). | Baseline to Week 52 | 
| Nasal Polyposis Surgery and/or Receiving Systemic Corticosteroids for Nasal Polyposis | Time to surgery decision and/or systemic corticosteroids for nasal polyposis, time to nasal polyposis surgery decision, and time to systemic corticosteroids for nasal polyposis up to Week 52. | Up to Week 52 | 
| Sinus Opacification | Change from baseline in Lund Mackay score evaluated by CT, sinus severity score by quantitative CT assessment, at 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). | Baseline to Week 52 | 
| Nasal Polyposis Symptom Diary Total Symptom Score | Change from baseline in bi-weekly mean Nasal Polyposis Symptom Diary Total Symptom Score at Week 52. The participant will complete an 11-item nasal polyposis symptom diary each morning throughout the screening, treatment and followup periods. The participant is asked to consider their experience with nasal polyposis/nasal polyps over the past 24hrs when responding to each question. Participants are 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) and symptom impacts (difficulty with sleeping due to nasal symptoms and difficulty with daily activities due to nasal symptoms). Participants report 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 is calculated by taking the sum of the 8 equally weighted symptom items. | Baseline to Week 52 | 
| Resolution/Near Complete Resolution of Nasal Polyps (defined as maximum NPS of 1 in each nostril) | Proportion of participants who achieve a maximum NPS of 1 in each nostril at Week 52. | At Week 52 | 
| Resolution/Near Complete Resolution of Nasal Polyps (defined as maximum NPS of 1 in each nostril) and Nasal Polyposis Symptom Diary Total Symptom Score response | Proportion of participants who achieve a maximum NPS of 1 in each nostril and Nasal Polyposis Symptom Diary Total Symptom Score response at Week 52. | At Week 52 | 
| Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) in Participants with Comorbid Asthma and Aspirin Exacerbated Respiratory Disease (AERD)/Nonsteroidal Anti-Inflammatory Drug Exacerbated Respiratory Disease (NSAID-ERD) | Change from baseline in pre-bronchodilator forced expiratory volume in 1 second at 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. | Baseline to Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic rhinosinusitis with nasal polyps, Nasal polyps, Nasal polyposis