Chronic Rhinosinusitis With Nasal Polyps
Conditions
Brief summary
This is a parallel group, Phase 3, 2-arm study for treatment. The purpose of this study is to evaluate dupilumab subcutaneous (SC) injections compared to placebo in Chinese adult participants with CRSwNP, on a background therapy with intranasal corticosteroids (budesonide nasal spray). Study details include: * The study duration will be up to 40 weeks. * The treatment duration will be up to 24 weeks. * The number of visits will be 7.
Detailed description
up to 40 weeks
Interventions
DRUGDupilumab
solution for subcutaneous injection
DRUGPlacebo
solution for subcutaneous injection
DRUGBudesonide
nasal spray (suspension)
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be at least 18 years of age at the time of signing the informed consent * Participants with bilateral sino-nasal polyposis that despite prior treatment with SCS anytime within the past 2 years; and/or who have a medical contraindication/intolerance to SCS; and/or had prior surgery for NP at Visit 1 have: 1. An endoscopic bilateral NPS at Visit 1 of at least 5 out of a maximum score of 8 (with a minimum score of 2 in each nasal cavity) as per central assessment 2. Ongoing symptoms (for at least 8 weeks before Visit 1) of: * Nasal congestion/blockade/obstruction with moderate or severe symptom severity (Score 2 or 3) at Visit 1 and a weekly average severity of greater than 1 at time of randomization (Visit 2) AND * Another symptom such as loss of smell, rhinorrhea (anterior/posterior) Note: Plan to enroll at least 85% (approximately 52) participants with CRSwNP meeting following criterion: • Participants with peripheral blood eosinophil count ≥300/mm3 * Contraceptive use should be consistent with the regulations regarding the methods of contraception for those participating in clinical studies * Capable of giving signed informed consent
Exclusion criteria
* Participants with conditions/concomitant diseases making them non-evaluable at Visit 1 or for the primary efficacy endpoint (ie, NPS) * Participants with nasal cavity malignant tumor and benign tumors (eg, papilloma, hemangioma, etc) * Participant with historical spirometry results which showed 50% or less of predicted normal of forced expiratory volume in one second (FEV1) * Diagnosed with; suspected of, or at high risk of endoparasitic infection, and/or use of antiparasitic drug within 2 weeks before Visit 1 or during the screening period * History of human immunodeficiency virus infection or positive HIV 1/2 serology at Visit 1 * Known or suspected immunodeficiency * Participants with active Tuberculosis (TB), non-tuberculous mycobacterial infection or a history of incompletely treated TB will be excluded from the study unless it is well documented by a specialist that the participant has been adequately treated and can now start treatment with a biologic agent, in the medical judgment of the Investigator and/or infectious disease specialist. Tuberculosis testing will be performed according to local guidelines if required by regulatory authorities or ethics boards, or if TB is suspected by the investigator * Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before Visit 1 or during the screening period * Active malignancy or history of malignancy within 5 years before the baseline visit, except completely treated in situ carcinoma of the cervix and completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin * Known or suspected alcohol and/or drug abuse * History of systemic hypersensitivity or anaphylaxis to dupilumab including any excipient * Participants meet any contraindications or warning on product labeling for budesonide nasal spray * Severe concomitant illness(es) that, in the Investigator's judgement, would adversely affect the participant's participation in the study. * Participants with any other medical or psychological condition including relevant laboratory or electrocardiogram (ECG) abnormalities at screening that, in the opinion of the Investigator, suggest a new and/or insufficiently understood disease, may present an unreasonable risk to the study participant as a result of his/her participation in this clinical trial, may make participant's participation unreliable, or may interfere with study assessments. The specific justification for participants excluded under this criterion will be noted in study documents (chart notes, case report form (CRF), etc) * Planned major surgical procedure during the participant's participation in this study * Participants who have taken: Biologic therapy/systemic immunosuppressant/immunomodulator within 4 weeks before Visit 1 or 5 half-lives, whichever is longer. Any investigational monoclonal antibody (mAb) within 5 half-lives or within 6 months before Visit 1 if the half-life is unknown. Anti-immunoglobulin E therapy (omalizumab) within 4 months prior to Visit 1. * Treatment with a live (attenuated) vaccine within 4 weeks prior to Visit 1 * Participants who are receiving leukotriene antagonists/modifiers within 4 weeks before V1 or 5 half-lives, whichever is longer, unless patient is on a continuous treatment for at least 4 weeks before Visit 1 * Initiation of allergen immunotherapy within 3 months prior to Visit 1 or a plan to begin therapy or change its dose during the run-in or randomized treatment period * Participants who have undergone any intranasal and/or sinus surgery (including polypectomy) within 6 months prior to Visit 1 or sino-nasal surgery changing the lateral wall structure of the nose making the evaluation of NPS impossible * Use of any prohibited medications and procedures during screening period or planned use during screening or study treatment period * Either intravenous immunoglobulin (IVIG) therapy and/or plasmapheresis within 4 weeks before Visit 1 * Current participation in any clinical trial of an investigational drug or device or participation within 3 months before V1 or 5 half-lives of the investigational compound, whichever is longer * Participation in a prior dupilumab clinical study or have been treated with commercially available dupilumab * Patients with any of the following result at the screening visit (Visit 1): Positive (or indeterminate) hepatitis B surface antigen (HBsAg) or, Positive total Hepatitis B core antibody (HBc Ab) confirmed by positive hepatitis B virus (HBV) DNA or, Positive HCV Ab confirmed by positive hepatitis C Virus (HCV) RNA. * noninvestigational medicinal product(NIMP) noncompliance at Visit 2 (\<80%) * Any condition that could make the participant noncompliant with the study procedures and daily assessment in the e-diary * Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized. * Participants not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures * Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals * Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Nasal Polyps Score at Week 24 | Baseline (Day 1) and Week 24 | The NPS was the sum of the right and left nostril scores and assessed by central video recordings of bilateral nasal endoscopy. For each nostril, NPS was graded based on polyp size which ranged from 0: no polyps, 1: small polyps in the middle meatus not reaching below the inferior border of the middle turbinate, 2: polyps reaching below the lower border of the middle turbinate, 3: large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate, 4: large polyps causing complete obstruction of the inferior nasal cavity. Total NPS was the sum of right and left nostril scores; ranged from 0 (no polyps) to 8 (large polyps). Higher scores indicated more severe disease. Baseline was defined as the last available value before randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Symptoms Score (TSS) at Week 24 | Baseline (Day -7 to Day -1) and Week 24 | The TSS was a reflective score of the worst symptom severity over the past 24 hours by the participant. It was assessed by the participant on a daily basis from visit 1 and throughout the study. It consisted of the sum of the following rhinosinusitis symptom questions: nasal congestion, decreased/loss of sense of smell, rhinorrhea (average of anterior/posterior nasal discharge); each assessed on 0 to 3 categorical scale, where 0: no symptoms, 1: mild symptoms, 2: moderate symptoms and 3: severe symptoms. The TSS was a composite score by summing the above symptom scores and ranged from 0 (no symptoms) to 9 (severe symptoms). Higher scores indicated greater overall symptom severity. The Week 24 analysis score was calculated as the average of all scores during the 4 weeks before Week 24. Baseline was defined as the average of the scores in the 7 days prior to randomization. |
| Change From Baseline in the Severity of Decreased/Loss of Smell at Week 24 | Baseline (Day -7 to Day -1) and Week 24 | The decreased/loss of sense of smell severity was a reflective score of the worst symptom severity over the past 24 hours. It was assessed by the participant on a daily basis from visit 1 and throughout the study, using an e-diary. It consisted of a 0 to 3 categorical scale, where 0: no symptoms, 1: mild symptoms, 2: moderate symptoms and 3: severe symptoms. Higher scores indicated more severe symptoms. The Week 24 analysis score was calculated as the average of all scores during the 4 weeks before Week 24. Baseline was defined as the average of the scores in the 7 days prior to randomization. |
| Change From Baseline in Nasal Congestion/Obstruction Score (NCS) at Week 24 | Baseline (Day -7 to Day -1) and Week 24 | The NCS was a patient reported outcome to evaluate nasal congestion/obstruction, a major clinical symptom in chronic rhinosinusitis phenotype with nasal polyps. The NCS was assessed by the participant on a daily basis from visit 1 and throughout the study. It consisted of a 0 to 3 categorical scale, where 0: no symptoms, 1: mild symptoms, 2: moderate symptoms and 3: severe symptoms. Higher scores indicated more severity. The Week 24 analysis score was calculated as the average of all scores during the 4 weeks before Week 24. Baseline was defined as the average of the scores in the 7 days prior to randomization. |
| Percentage of Participants Who Received Systemic Corticosteroid (SCS) or Underwent Nasal Polyposis (NP) Surgery During the Study Treatment | From randomization (Day 1) up to last dose of study treatment + 14 days, a maximum of 168 days | SCS for rescue treatment of nasal polyps or for another reason were prescribed to the participant by the site. For participants who had a surgery or had a scheduled date for surgery for NP, the reason (worsening signs and/or symptoms during the study), the expected or actual surgery date, the type and outcome of surgery was recorded in a specific e-case report form page. Percentage of participants who received SCS or underwent NP surgery during the study treatment are presented. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Treatment-Emergent Adverse Events Leading to Treatment Discontinuation | From first dose of study treatment (Day 1) up to last dose of study treatment + 98 days, a maximum of 252 days | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that developed, worsened or became serious during the TE period. |
| Change From Baseline in Total Score of 22-Items Sinonasal Outcome Test (SNOT-22) at Week 24 | Baseline (Day 1) and Week 24 | The SNOT-22 was a validated 22-items questionnaire to assess the impact of chronic rhinosinusitis on health-related quality of life (HRQoL) with a recall period of 2 weeks. There were 5 domains that could be described within SNOT-22, including nasal, ear, sleep, general and practical, and emotional; each domain was scored on a 5-category scale which ranged from 0: no problem to 5: problem as bad as it can be. The total score was the sum of response to each of the 22 questions and ranged from 0 (no disease) to 110 (worst disease), higher scores indicated worse HRQoL. Baseline was defined as the last available value before randomization. |
Countries
China
Participant flow
Recruitment details
The study was conducted at 18 centers in China. A total of 151 participants were screened from 16 May 2023 to 27 February 2024, of which 88 were screen failures. Screen failures were mainly due to not meeting the eligibility criteria.
Pre-assignment details
A total of 63 participants were randomized in a 1:1 ratio to receive either matching placebo or dupilumab. Randomization was stratified by screening blood eosinophil count (\>=300 cells per cubic millimeter \[/mm\^3\] or \<300 cells/mm\^3).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to dupilumab SC injection q2w from Day 1 up to 24 weeks. | 32 |
| Dupilumab 300 mg q2w Participants received dupilumab 300 mg SC injection q2w from Day 1 up to 24 weeks. | 31 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Dupilumab 300 mg q2w | Total |
|---|---|---|---|
| Age, Continuous | 49.4 years STANDARD_DEVIATION 11.3 | 47.1 years STANDARD_DEVIATION 12.1 | 48.3 years STANDARD_DEVIATION 11.6 |
| Nasal Polyps Score (NPS) | 5.84 score on a scale STANDARD_DEVIATION 1.6 | 5.53 score on a scale STANDARD_DEVIATION 1.41 | 5.69 score on a scale STANDARD_DEVIATION 1.51 |
| Race/Ethnicity, Customized Asian | 32 Participants | 31 Participants | 63 Participants |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Male | 19 Participants | 17 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 31 |
| other Total, other adverse events | 11 / 32 | 15 / 31 |
| serious Total, serious adverse events | 0 / 32 | 4 / 31 |
Outcome results
Primary
Change From Baseline in Nasal Polyps Score at Week 24
The NPS was the sum of the right and left nostril scores and assessed by central video recordings of bilateral nasal endoscopy. For each nostril, NPS was graded based on polyp size which ranged from 0: no polyps, 1: small polyps in the middle meatus not reaching below the inferior border of the middle turbinate, 2: polyps reaching below the lower border of the middle turbinate, 3: large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate, 4: large polyps causing complete obstruction of the inferior nasal cavity. Total NPS was the sum of right and left nostril scores; ranged from 0 (no polyps) to 8 (large polyps). Higher scores indicated more severe disease. Baseline was defined as the last available value before randomization.
Time frame: Baseline (Day 1) and Week 24
Population: The intent-to-treat (ITT) population included all randomized participants analyzed according to the treatment group allocated by randomization, regardless of whether the treatment kit was used or not.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Nasal Polyps Score at Week 24 | -0.50 score on a scale | Standard Error 0.3 |
| Dupilumab 300 mg q2w | Change From Baseline in Nasal Polyps Score at Week 24 | -2.34 score on a scale | Standard Error 0.3 |
p-value: <0.000195% CI: [-2.53, -1.15]ANCOVA
Secondary
Change From Baseline in Nasal Congestion/Obstruction Score (NCS) at Week 24
The NCS was a patient reported outcome to evaluate nasal congestion/obstruction, a major clinical symptom in chronic rhinosinusitis phenotype with nasal polyps. The NCS was assessed by the participant on a daily basis from visit 1 and throughout the study. It consisted of a 0 to 3 categorical scale, where 0: no symptoms, 1: mild symptoms, 2: moderate symptoms and 3: severe symptoms. Higher scores indicated more severity. The Week 24 analysis score was calculated as the average of all scores during the 4 weeks before Week 24. Baseline was defined as the average of the scores in the 7 days prior to randomization.
Time frame: Baseline (Day -7 to Day -1) and Week 24
Population: The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization, regardless of whether the treatment kit was used or not.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Nasal Congestion/Obstruction Score (NCS) at Week 24 | -0.52 score on a scale | Standard Error 0.18 |
| Dupilumab 300 mg q2w | Change From Baseline in Nasal Congestion/Obstruction Score (NCS) at Week 24 | -1.06 score on a scale | Standard Error 0.18 |
p-value: 0.012695% CI: [-0.97, -0.12]ANCOVA
Secondary
Change From Baseline in the Severity of Decreased/Loss of Smell at Week 24
The decreased/loss of sense of smell severity was a reflective score of the worst symptom severity over the past 24 hours. It was assessed by the participant on a daily basis from visit 1 and throughout the study, using an e-diary. It consisted of a 0 to 3 categorical scale, where 0: no symptoms, 1: mild symptoms, 2: moderate symptoms and 3: severe symptoms. Higher scores indicated more severe symptoms. The Week 24 analysis score was calculated as the average of all scores during the 4 weeks before Week 24. Baseline was defined as the average of the scores in the 7 days prior to randomization.
Time frame: Baseline (Day -7 to Day -1) and Week 24
Population: The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization, regardless of whether the treatment kit was used or not.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Severity of Decreased/Loss of Smell at Week 24 | -0.23 score on a scale | Standard Error 0.2 |
| Dupilumab 300 mg q2w | Change From Baseline in the Severity of Decreased/Loss of Smell at Week 24 | -0.86 score on a scale | Standard Error 0.2 |
p-value: 0.007295% CI: [-1.08, -0.17]ANCOVA
Secondary
Change From Baseline in Total Score of 22-Items Sinonasal Outcome Test (SNOT-22) at Week 24
The SNOT-22 was a validated 22-items questionnaire to assess the impact of chronic rhinosinusitis on health-related quality of life (HRQoL) with a recall period of 2 weeks. There were 5 domains that could be described within SNOT-22, including nasal, ear, sleep, general and practical, and emotional; each domain was scored on a 5-category scale which ranged from 0: no problem to 5: problem as bad as it can be. The total score was the sum of response to each of the 22 questions and ranged from 0 (no disease) to 110 (worst disease), higher scores indicated worse HRQoL. Baseline was defined as the last available value before randomization.
Time frame: Baseline (Day 1) and Week 24
Population: The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization, regardless of whether the treatment kit was used or not.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Total Score of 22-Items Sinonasal Outcome Test (SNOT-22) at Week 24 | -11.58 score on a scale | Standard Error 3.14 |
| Dupilumab 300 mg q2w | Change From Baseline in Total Score of 22-Items Sinonasal Outcome Test (SNOT-22) at Week 24 | -21.10 score on a scale | Standard Error 3.14 |
p-value: 0.010495% CI: [-16.81, -2.24]ANCOVA
Secondary
Change From Baseline in Total Symptoms Score (TSS) at Week 24
The TSS was a reflective score of the worst symptom severity over the past 24 hours by the participant. It was assessed by the participant on a daily basis from visit 1 and throughout the study. It consisted of the sum of the following rhinosinusitis symptom questions: nasal congestion, decreased/loss of sense of smell, rhinorrhea (average of anterior/posterior nasal discharge); each assessed on 0 to 3 categorical scale, where 0: no symptoms, 1: mild symptoms, 2: moderate symptoms and 3: severe symptoms. The TSS was a composite score by summing the above symptom scores and ranged from 0 (no symptoms) to 9 (severe symptoms). Higher scores indicated greater overall symptom severity. The Week 24 analysis score was calculated as the average of all scores during the 4 weeks before Week 24. Baseline was defined as the average of the scores in the 7 days prior to randomization.
Time frame: Baseline (Day -7 to Day -1) and Week 24
Population: The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization, regardless of whether the treatment kit was used or not.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Total Symptoms Score (TSS) at Week 24 | -1.07 score on a scale | Standard Error 0.43 |
| Dupilumab 300 mg q2w | Change From Baseline in Total Symptoms Score (TSS) at Week 24 | -2.75 score on a scale | Standard Error 0.43 |
p-value: 0.000895% CI: [-2.67, -0.69]ANCOVA
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Treatment-Emergent Adverse Events Leading to Treatment Discontinuation
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that developed, worsened or became serious during the TE period.
Time frame: From first dose of study treatment (Day 1) up to last dose of study treatment + 98 days, a maximum of 252 days
Population: The safety population included all participants randomly assigned to study treatment and who took at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Treatment-Emergent Adverse Events Leading to Treatment Discontinuation | TEAEs | 20 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Treatment-Emergent Adverse Events Leading to Treatment Discontinuation | TESAEs | 0 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Treatment-Emergent Adverse Events Leading to Treatment Discontinuation | TEAEs leading to treatment discontinuation | 0 Participants |
| Dupilumab 300 mg q2w | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Treatment-Emergent Adverse Events Leading to Treatment Discontinuation | TEAEs | 23 Participants |
| Dupilumab 300 mg q2w | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Treatment-Emergent Adverse Events Leading to Treatment Discontinuation | TESAEs | 4 Participants |
| Dupilumab 300 mg q2w | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs) and Treatment-Emergent Adverse Events Leading to Treatment Discontinuation | TEAEs leading to treatment discontinuation | 0 Participants |
Secondary
Percentage of Participants Who Received Systemic Corticosteroid (SCS) or Underwent Nasal Polyposis (NP) Surgery During the Study Treatment
SCS for rescue treatment of nasal polyps or for another reason were prescribed to the participant by the site. For participants who had a surgery or had a scheduled date for surgery for NP, the reason (worsening signs and/or symptoms during the study), the expected or actual surgery date, the type and outcome of surgery was recorded in a specific e-case report form page. Percentage of participants who received SCS or underwent NP surgery during the study treatment are presented.
Time frame: From randomization (Day 1) up to last dose of study treatment + 14 days, a maximum of 168 days
Population: The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization, regardless of whether the treatment kit was used or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Received Systemic Corticosteroid (SCS) or Underwent Nasal Polyposis (NP) Surgery During the Study Treatment | 9.4 percentage of participants |
| Dupilumab 300 mg q2w | Percentage of Participants Who Received Systemic Corticosteroid (SCS) or Underwent Nasal Polyposis (NP) Surgery During the Study Treatment | 0 percentage of participants |