Dupilumab in CRSsNP (Liberty CRSsNP ORION)
Study Details
Study Description
Brief Summary
Primary Objective:
Part A and B: To evaluate the efficacy of dupilumab as assessed by the reduction at Week 24 in sinus opacification on computerized tomography (CT) scan and sinus total symptom score (sTSS) compared to placebo
Secondary Objectives:
Part A
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To evaluate the efficacy of dupilumab as assessed by the reduction at Week 52 in sinus opacification on CT scan and total symptom score (sTSS) compared to placebo
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To evaluate the efficacy of dupilumab in improving CRSsNP symptoms at Weeks 24 and 52 compared to placebo
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To evaluate the effect of dupilumab on health related quality of life at Weeks 24 and 52 (HRQoL) compared to placebo
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To evaluate the effect of dupilumab on CRSsNP overall disease severity at Weeks 24 and 52 compared to placebo
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To evaluate the effect of dupilumab at Weeks 24 and 52 in the subgroups of participants with comorbid asthma compared to placebo
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To evaluate the ability of dupilumab to reduce the incidence of participants with CRSsNP worsening/acute sinusitis who require treatment with antibiotics, systemic corticosteroids (SCS) or sinus surgery compared to placebo
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To evaluate the effects of dupilumab on transcriptomic signatures associated with CRSsNP and type 2 inflammation
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To evaluate the effect of dupilumab in the subgroup of participants with screening blood eosinophils count ≥300 cells/mm3 compared to placebo
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To evaluate the safety and tolerability of dupilumab in CRSsNP patients compared to placebo
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To evaluate the pharmacokinetics (PK) of dupilumab in CRSsNP patients compared to placebo
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Assessment of immunogenicity to dupilumab over time compared to placebo
Part B
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To evaluate the efficacy of dupilumab in improving CRSsNP symptoms at Week 24 compared to placebo in patients
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To evaluate the effect of dupilumab on health related quality of life (HRQoL) compared to placebo
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To evaluate the effect of dupilumab on CRSsNP overall disease severity compared to placebo
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To evaluate the effect of dupilumab in the subgroups of participants with comorbid asthma compared to placebo
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To evaluate the ability of dupilumab to reduce the incidence of participants with CRSsNP worsening/acute sinusitis who require treatment with antibiotics, SCS, or sinus surgery compared to placebo
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To evaluate the effects of dupilumab on transcriptomic signatures associated with CRSsNP and type 2 inflammation
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To evaluate the safety and tolerability of dupilumab in CRSsNP patients compared to placebo
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To evaluate the pharmacokinetics (PK) of dupilumab in CRSsNP patients compared to placebo
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Assessment of immunogenicity to dupilumab over time compared to placebo
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
The duration of study for each participant will include 2-4 weeks of screening period, randomized investigational medicinal product (IMP) intervention period (52 weeks in Part A and 24 weeks in Part B) and 12 weeks of follow-up period.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part A and B: Dupilumab Dupilumab administered every 2 weeks. |
Drug: Dupilumab SAR231893
Pharmaceutical form:Injection solution Route of administration: Subcutaneous
|
| Placebo Comparator: Part A and B: Matching placebo Placebo administered every 2 weeks |
Drug: Placebo
Pharmaceutical form:Injection solution Route of administration: Subcutaneous
|
Outcome Measures
Primary Outcome Measures
- Part A and B: Change from baseline to Week 24 in opacification of sinuses assessed by CT scan using the Lund Mackay (LMK) score [Baseline to Week 24]
LMK total score is based on assessment of the CT scan findings for each sinus area. The extent of opacification is rated between 0 (normal) to 24 (total opacification).
- Part A and B: Change from baseline to Week 24 in sTSS [Baseline to Week 24]
The sinus Total Symptom Score (sTSS) is a composite score derived from the following individual items: nasal congestion (NC), anterior/posterior rhinorrhea, and facial pain/pressure. The total score ranges from 0-9. Higher scores on sTSS indicate greater overall symptom severity.
Secondary Outcome Measures
- Part A: Change from baseline to Week 52 in opacification of sinuses assessed by CT scan using the LMK score [Baseline to Week 52]
LMK total score is based on assessment of the CT scan findings for each sinus area. The extent of opacification is rated between 0 (normal) to 24 (total opacification).
- Part A: Change from baseline to Week 52 in sTSS [Baseline to Week 52]
The sTSS is a composite score derived from the following individual items: NC, anterior/posterior rhinorrhea, and facial pain/pressure. The total score ranges from 0-9. Higher scores on sTSS indicate greater overall symptom severity.
- Part A and B: Change from baseline in NC symptom severity score [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
NC symptom severity scores are scored from 0 ("No symptoms") to 3 ("Severe symptoms - symptoms that are hard to tolerate, cause interference with activities or daily living").
- Part A and B: Change from baseline in anterior/posterior rhinorrhea severity score [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
Anterior/posterior rhinorrhea severity scores are scored from 0 ("No symptoms") to 3 ("Severe symptoms - symptoms that are hard to tolerate, cause interference with activities or daily living").
- Part A and B: Change from baseline in facial pain/pressure severity score [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
Facial pain/pressure severity scores are scored from 0 ("No symptoms") to 3 ("Severe symptoms - symptoms that are hard to tolerate, cause interference with activities or daily living").
- Part A and B: Change from baseline in loss of smell symptom severity score [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
Loss of smell symptom severity scores are scored from 0 ("No symptoms") to 3 ("Severe symptoms - symptoms that are hard to tolerate, cause interference with activities or daily living").
- Part A and B: Change from baseline in University of Pennsylvania smell identification test (UPSIT) [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
The UPSIT score ranges from 0 to 40, with 40 being the best possible score.
- Part A and B: Change from baseline in Sino-Nasal Outcome Test-22 item (SNOT-22) [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
SNOT-22 is a patient-reported outcome (PRO) questionnaire. Score ranges from 0 to 110 with higher score indicating greater rhinosinusitis related health burden.
- Part A and B: Change from baseline in rhinosinusitis severity visual analog scale (VAS) [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
VAS score ranges from 0 ('not troublesome') to 10 ('worst thinkable troublesome').
- Part A and B: Change from baseline in forced expiratory volume (FEV1) in CRSsNP with asthma population [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
Change from baseline in forced expiratory volume (FEV1) in CRSsNP with asthma population.
- Part A and B: Change from baseline in asthma control questionnaire 6 items (ACQ-6) in CRSsNP with asthma population [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
The asthma control questionnaire 6-items (ACQ-6) was designed to measure both the adequacy of asthma control and the change in asthma control. ACQ-6 global score ranges from 0 (totally controlled) to 6 (severely uncontrolled). A higher score indicates lower asthma control.
- Part A and B: Change from baseline in opacification of sinuses assessed by CT scan using the LMK score in CRSsNP with asthma population [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
LMK total score is based on assessment of the CT scan findings for each sinus area. The extent of opacification is rated between 0 (normal) to 24 (total opacification).
- Part A and B: Change from baseline in sTSS in CRSsNP with asthma population [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
The sTSS is a composite score derived from the following individual items: NC, anterior/posterior rhinorrhea, and facial pain/pressure. The total score ranges from 0-9. Higher scores on sTSS indicate greater overall symptom severity.
- Part A and B: Proportion of participants with CRSsNP worsening/acute sinusitis during the planned study treatment period [Part A: Baseline to Week 52 Part B: Baseline to Week 24]
CRSsNP worsening/acute sinusitis is defined as worsening of any CRS symptoms that requires initiation of rescue therapy.
- Part A and B: Annualized rate of SCS course during the planned study treatment period [Part A: Baseline to Week 52 Part B: Baseline to Week 24]
A course of SCS is considered continuous if treatment is separated by less than 7 days.
- Part A and B: Normalized Enrichment Score (NES) for the relative change from baseline in the type 2 inflammation transcriptome signature [Part A: Baseline to Week 24 and 52 Part B: Baseline to Week 24]
Normalized Enrichment Score (NES) reflects the degree to which the activity level of a set of transcripts is overrepresented at the extremes (top or bottom) of the entire ranked list of transcripts within a sample and is normalized by accounting for the number of transcripts in the set.
- Part A: Change from baseline to Weeks 24 and 52 in opacification of sinuses assessed by CT scan using LMK score in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
LMK total score is based on assessment of the CT scan findings for each sinus area. The extent of opacification is rated between 0 (normal) to 24 (total opacification).
- Part A: Change from baseline to Weeks 24 and 52 in sTSS in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
The sTSS is a composite score derived from the following individual items: NC, anterior/posterior rhinorrhea, and facial pain/pressure. The total score ranges from 0-9. Higher scores on sTSS indicate greater overall symptom severity.
- Part A: Change from baseline in NC symptom severity score in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
NC symptom severity scores are scored from 0 ("No symptoms") to 3 ("Severe symptoms - symptoms that are hard to tolerate, cause interference with activities or daily living").
- Part A: Change from baseline in anterior/posterior rhinorrhea severity score in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
Anterior/posterior rhinorrhea severity scores are scored from 0 ("No symptoms") to 3 ("Severe symptoms - symptoms that are hard to tolerate, cause interference with activities or daily living").
- Part A: Change from baseline in facial pain/pressure severity score in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
Facial pain/pressure severity scores are scored from 0 ("No symptoms") to 3 ("Severe symptoms - symptoms that are hard to tolerate, cause interference with activities or daily living").
- Part A: Change from baseline in loss of smell symptom severity score in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
Loss of smell symptom severity scores are scored from 0 ("No symptoms") to 3 ("Severe symptoms - symptoms that are hard to tolerate, cause interference with activities or daily living").
- Part A: Change from baseline in UPSIT in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
The UPSIT score ranges from 0 to 40, with 40 being the best possible score.
- Part A: Change from baseline in SNOT-22 in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
SNOT-22 is a patient-reported outcome (PRO) questionnaire. Score ranges from 0 to 110 with higher score indicating greater rhinosinusitis related health burden.
- Part A: Change from baseline in rhinosinusitis severity VAS in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
VAS score ranges from 0 ('not troublesome') to 10 ('worst thinkable troublesome').
- Part A: Proportion of participants with CRSsNP worsening/acute sinusitis during the planned study treatment period in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
CRSsNP worsening/acute sinusitis is defined as worsening of any CRS symptoms that requires initiation of rescue therapy.
- Part A: Annualized rate of SCS course during the planned study treatment period in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
A course of SCS is considered continuous if treatment is separated by less than 7 days.
- Part A: NES for the relative change from baseline in the type 2 inflammation transcriptome signature in the screening blood eosinophil count ≥300 cells/mm3 population [Baseline to Week 24 and 52]
Normalized Enrichment Score (NES) reflects the degree to which the activity level of a set of transcripts is overrepresented at the extremes (top or bottom) of the entire ranked list of transcripts within a sample and is normalized by accounting for the number of transcripts in the set.
- Part A and B: Incidence of treatment-emergent adverse events (TEAEs), of treatment-emergent serious AEs (TESAEs), and TEAEs leading to treatment discontinuation [Part A: Baseline to Week 64 Part B: Baseline to Week 36]
Incidence of treatment-emergent adverse events (TEAEs), of treatment-emergent serious AEs (TESAEs), and TEAEs leading to treatment discontinuation.
- Part A and B: Dupilumab concentration in serum [Part A: Baseline to Week 52 Part B: Baseline to Week 24]
Dupilumab concentration in serum.
- Part A and B: Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time [Part A: Baseline to Week 64 Part B: Baseline to Week 36]
Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Part A only: Participant must be at least 18 years of age at the time of signing the informed consent form (ICF).
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Part B only: Participant must be at least 12 years of age (or the minimum legal age for adolescents in the country of the investigational site) at the time of signing the ICF.
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Participants must have bilateral inflammation of paranasal sinuses in CT scan with LMK ≥8 and bilateral ethmoid opacification before randomization.
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Participants must have ongoing symptoms of loss of smell and rhinorrhea (anterior/posterior) of any severity, with or without facial pain/pressure for at least 12 consecutive weeks by Visit 1.
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Participants must have ongoing symptoms of nasal congestion (NC)/obstruction at least 12 consecutive weeks before Visit 1 and a NC score of ≥ 2 at Visit 1 (day score) and Visit 2 (weekly average score).
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Participants must have sTSS (NC, rhinorrhea, facial pain/pressure) ≥5 at Visit 1 (day score) and Visit 2 (weekly average score).
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Participants must have one of the 2 following features:
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Prior sinonasal surgery for CRS,
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Treatment with SCS therapy for CRS as defined by any dose and duration within the prior 2 years before screening (Visit 1) or intolerance/contraindication to SCS.
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For Part B only: participants who have a blood eosinophil count ≥300 cells/mm3 at Screening
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Body weight ≥30 kg.
Exclusion Criteria:
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Patients with nasal conditions/concomitant nasal diseases such as nasal polyposis in endoscopy at Visit 1 or with history of nasal polyposis etc., making them non-evaluable at Visit 1 or for the primary efficacy
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Nasal cavity malignant tumor and benign tumors.
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Forced expiratory volume (FEV1) ≤50% of predicted normal at Visit 1.
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Radiologic suspicion or confirmed invasive or expansive fungal rhinosinusitis.
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Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect participation in the study
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Active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis unless documented adequately treated.
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Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection
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Known or suspected immunodeficiency
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History of malignancy within 5 years before Visit 1, except completely treated in situ carcinoma of the cervix, and completely treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin.
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Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before the Screening Visit 1 or during the screening period.
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History of systemic hypersensitivity or anaphylaxis to dupilumab or any of its excipients.
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Patients in prior dupilumab clinical trial or have been treated with commercially available dupilumab within 12 months or who discontinued dupilumab use due to adverse event.
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Patients who are treated with intranasal corticosteroid drops; intranasal steroid emitting devices/stents; nasal spray using exhalation delivery system, such as Xhance™, during screening period.
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Participants on unstable dose of intranasal corticosteroids (INCS) spray 4 weeks prior to Screening Visit (Visit1) and during screening period.
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Patients who have undergone sinus intranasal surgery (including polypectomy) within 6 months prior to Visit 1.
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Patients who have taken:
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Biologic therapy/systemic immunosuppressant to treat inflammatory disease or autoimmune disease within 5 half-lives prior to Visit 1
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Any investigational mAb within 5 half-lives prior to Visit 1
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Anti-IgE therapy (omalizumab) within 4 months prior to Visit 1.
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Treatment with a live (attenuated) vaccine within 4 weeks prior to Visit 1
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Leukotriene antagonists/modifiers unless patient is on a continuous treatment for at least 30 days prior to Visit 1.
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Initiation of allergen immunotherapy within 3 months prior to Visit 1 or a plan to begin therapy or change its dose during the screening or treatment period.
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Patients received SCS during screening period (between Visit 1 and Visit 2).
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Either intravenous immunoglobulin therapy and/or plasmapheresis within 30 days prior to Screening Visit (Visit 1).
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Investigational Site Number :8400010 | Roseville | California | United States | 95661 |
| 2 | Investigational Site Number :8400008 | Denver | Colorado | United States | 80206 |
| 3 | Investigational Site Number :8400003 | Denver | Colorado | United States | 80230 |
| 4 | Investigational Site Number :8400002 | Louisville | Kentucky | United States | 40220 |
| 5 | Investigational Site Number :8400016 | Columbia | Missouri | United States | 65212 |
| 6 | Investigational Site Number :8400007 | Papillion | Nebraska | United States | 68046 |
| 7 | Investigational Site Number :8400004 | Tulsa | Oklahoma | United States | 74136 |
| 8 | Investigational Site Number :8400014 | Tulsa | Oklahoma | United States | 74137 |
| 9 | Investigational Site Number :8400006 | Dallas | Texas | United States | 75231 |
| 10 | Investigational Site Number :8400009 | Norfolk | Virginia | United States | 23507 |
| 11 | Investigational Site Number :0560003 | Bruxelles | Belgium | 1200 | |
| 12 | Investigational Site Number :0560002 | Gent | Belgium | 9000 | |
| 13 | Investigational Site Number :0560001 | Leuven | Belgium | 3000 | |
| 14 | Investigational Site Number :1240010 | Hamilton | Ontario | Canada | L8L 2X2 |
| 15 | Investigational Site Number :1240007 | Kingston | Ontario | Canada | K7L 2V7 |
| 16 | Investigational Site Number :1240001 | Montreal | Quebec | Canada | H2X 3E4 |
| 17 | Investigational Site Number :1240012 | Montreal | Quebec | Canada | H4A 3J1 |
| 18 | Investigational Site Number :1240002 | Trois-Rivieres | Quebec | Canada | G8T 7A1 |
| 19 | Investigational Site Number :1240005 | Quebec | Canada | G1V 4G5 | |
| 20 | Investigational Site Number :1240003 | Quebec | Canada | G1V 4W2 | |
| 21 | Investigational Site Number :1520001 | Santiago | Reg Metropolitana De Santiago | Chile | 8207257 |
| 22 | Investigational Site Number :1560001 | Beijing | China | 100730 | |
| 23 | Investigational Site Number :1560013 | Changsha | China | 410013 | |
| 24 | Investigational Site Number :3480003 | Budapest | Hungary | 1083 | |
| 25 | Investigational Site Number :3480004 | Budapest | Hungary | 1115 | |
| 26 | Investigational Site Number :3480001 | Pécs | Hungary | 7621 | |
| 27 | Investigational Site Number :3480002 | Szeged | Hungary | 6725 | |
| 28 | Investigational Site Number :6200002 | Aveiro | Portugal | 3810-501 | |
| 29 | Investigational Site Number :6200001 | Guimarães | Portugal | 4810-061 | |
| 30 | Investigational Site Number :6200003 | Matosinhos | Portugal | 4464-513 | |
| 31 | Investigational Site Number :6430006 | Moscow | Russian Federation | 119002 | |
| 32 | Investigational Site Number :6430005 | Moscow | Russian Federation | 121359 | |
| 33 | Investigational Site Number :6430002 | St-Petersburg | Russian Federation | 197022 | |
| 34 | Investigational Site Number :6430003 | St-Petersburg | Russian Federation | 197022 | |
| 35 | Investigational Site Number :6430001 | Stavropol | Russian Federation | 355020 | |
| 36 | Investigational Site Number :7240002 | Sevilla | Andalucia | Spain | 41009 |
| 37 | Investigational Site Number :7240001 | Barcelona | Barcelona [Barcelona] | Spain | 08036 |
| 38 | Investigational Site Number :7240007 | Santander | Cantabria | Spain | 39008 |
| 39 | Investigational Site Number :7240004 | Jerez de la Frontera | Cádiz | Spain | 11407 |
| 40 | Investigational Site Number :7240006 | Santiago de Compostela | Galicia [Galicia] | Spain | 15706 |
| 41 | Investigational Site Number :7240005 | Madrid / Madrid | Madrid, Comunidad De | Spain | 28040 |
| 42 | Investigational Site Number :7240009 | Madrid | Madrid, Comunidad De | Spain | 28027 |
| 43 | Investigational Site Number :7240008 | Pamplona | Navarra | Spain | 31008 |
| 44 | Investigational Site Number :7520001 | Stockholm | Sweden | 171 76 | |
| 45 | Investigational Site Number :8040005 | Dnipro | Ukraine | 49006 | |
| 46 | Investigational Site Number :8040001 | Ivano-Frankivsk | Ukraine | 76018 | |
| 47 | Investigational Site Number :8040004 | Kharkiv | Ukraine | 61166 | |
| 48 | Investigational Site Number :8040008 | Kyiv | Ukraine | 01033 | |
| 49 | Investigational Site Number :8040002 | Kyiv | Ukraine | 03680 | |
| 50 | Investigational Site Number :8040007 | Kyiv | Ukraine | 04050 |
Sponsors and Collaborators
- Sanofi
- Regeneron Pharmaceuticals
Investigators
- Study Director: Clinical Sciences & Operations, Sanofi
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- EFC16723
- 2020-003117-35
- U1111-1246-7522