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A randomized double-blind placebo-controlled parallel group study assessing the efficacy and safety of dupilumab in patients with Allergic Fungal Rhinosinusitis (AFRS)

Dupilumab in Allergic Fungal Rhinosinusitis (AFRS)

62

The mean (standard deviation [SD]) age of the randomized population was 39.8 (16.0) years. A total of 45 (72.6%) male and 17 (27.4%) female participants were included in the study, most of them were White (27 [43.5%]) or Asian (25 [40.3%]); 8 (12.9%) were Black or African American.

- Randomized: 62 (placebo: 29, dupilumab: 33) - Randomized and exposed: 61 (placebo: 28, dupilumab: 33) - Completed the study intervention period: 49 (placebo: 20, dupilumab: 29) - Completed the study period: 45 (placebo: 18, dupilumab: 27) In the dupilumab group, participants received dupilumab depending on the weight at screening via subcutaneous injection for 52 weeks as follows: - 300 mg every 2 weeks (q2w) for all adults and adolescents/children weighing >=60 kg - 200 mg q2w for adolescents/children weighing >=30 kg and <60 kg - 300 mg every 4 weeks (q4w) for adolescents/children weighing >=15 kg and <30 kg

Overall, 23 (69.7%) participants in the dupilumab group and 22 (78.6%) participants in the placebo group experienced at least 1 TEAE. The most frequent preferred term (PT) was allergic fungal rhinosinusitis with a lower incidence in the dupilumab group than in the placebo group (1 [3.0%] participants in the dupilumab group versus 8 [28.6%] participants in the placebo group). There were no treatment-emergent SAEs reported in the dupilumab group. Treatment-emergent SAEs were reported in 2 (7.1%) participants in the placebo group (ureterolithiasis in 1 participant and allergic fungal rhinosinusitis and infection in 1 participant). No participants died during this study.

Primary endpoint: The primary endpoint of change from baseline to Week 52 in sinus opacification as assessed by sinus CT scan using the LMK score was both substantial and statistically significant. Least squares (LS) mean change (95% confidence interval [CI]) for dupilumab versus placebo was -7.36 (-9.38 to -5.35) in participants with AFRS. Secondary endpoints: Dupilumab also showed improvements versus placebo for the multiplicity-controlled secondary endpoints: - For change from baseline in monthly average nasal congestion/obstruction score from the Nasal Symptom Diary at Week 24, the LS mean difference (95% CI) versus placebo was -0.87 (-1.18 to -0.56). For change from baseline in monthly average nasal congestion/obstruction score from the Nasal Symptom Diary at Week 52, the LS mean difference (95% CI) versus placebo was -1.40 (-1.77 to -1.02). - For change from baseline in endoscopic nasal polyp score (NPS) at Week 24, the LS mean difference (95% CI) versus placebo was -2.36 (-3.31 to -1.41). For change from baseline in endoscopic NPS at Week 52, the LS mean difference (95% CI) versus placebo was -2.77 (-3.82 to -1.72). - For improvement in LMK score from baseline at Week 24, the LS mean difference (95% CI) versus placebo was -5.45 (-7.48 to -3.43). - For change from baseline in monthly average TSS derived from the Nasal Symptom Diary at Week 24, the LS mean difference (95% CI) versus placebo was -2.18 (-3.04 to -1.32) - For change from baseline in UPSIT at Week 24, the LS mean difference (95% CI) versus placebo was 4.46 (0.22 to 8.71). - For change from baseline in the score of decreased/loss of smell using the Nasal Symptom Diary at Week 24, the LS mean difference (95% CI) versus placebo was -0.89 (-1.29 to -0.49). - For change from baseline in SNOT-22 total score at Week 24, the LS mean difference (95% CI) versus placebo was -15.11 (-25.15 to -5.07). For change from baseline in SNOT-22 total score at Week 52, the LS mean difference (95% CI) versus placebo was -17.30 (-26.86 to -7.74). - For change from baseline to Week 52 in three-dimensional CT total volume occupied by disease in all sinuses (%), the LS mean difference (95% CI) versus placebo was -36.31 (-45.59 to -27.03). - For proportion of participants who receive SCS and/or undergo/plan to undergo surgery for AFRS during the planned study intervention period, the risk mean difference (%) (95% CI) versus placebo was -29.1% (-46.42 to -11.79). - For percent change from baseline in total immunoglobulin E (IgE) in serum at Week 52, the LS mean difference (95% CI) versus placebo was -79.32 (-152.65 to -6.00).

A total of 62 participants were randomized (dupilumab: 33, placebo: 29). Treatment with dupilumab resulted in clinically meaningful and statically significant beneficial effects across all aspects of AFRS including radiographic, endoscopic, clinical, sense of smell, health-related quality of life, use of rescue with SCS/surgery, and type 2 inflammatory biomarker related outcome measures. Dupilumab was well tolerated with an acceptable safety profile in participants aged 6 years and older with AFRS.

Yes

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

https://jrct.mhlw.go.jp/latest-detail/jRCT2041210031

Obara Kentaro

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

clinical-trials-jp@sanofi.com

Clinical Study Unit

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

+81-3-6301-3670

clinical-trials-jp@sanofi.com

Complete

Aug. 15, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1) Participant must be at least 6 years of age (or the minimum legal age for adolescents in the country of the investigational site) at the time of signing the informed consent.
2) Participants with the diagnosis of AFRS adapted from criteria by Bent and Kuhn (meeting all):
- IgE mediated inflammatory response to fungal hyphae (specific IgE serology or skin test)
Evidence of sensitization to fungus by skin testing (at screening or documented historical positive skin test in the previous 12 months), or positive fungal-specific IgE in serum at screening.
- Nasal polyposis confirmed by nasal endoscopy at screening.
- Characteristic CT signs to be performed during screening period and can include any of the below signs as assessed by central reader:
* hyperdensities
* bony demineralization
* bone erosion of sinus
- Eosinophilic mucin/mucus identified within 5 years prior to screening or at screening with or without positive fungal stain.
3) AFRS patients with the following:
- An endoscopic Nasal Polyp Score (NPS) of at least 2 out of 4 for unilateral polyps or 3 out of 8 for bilateral polyps at Visit 1 (central reading) and Visit 2 (local reading) and,
- Sinus opacification in CT scan with an Lund Mackay (LMK) score of 9 for patients with unilateral polyps or 12 for patients with bilateral polyps during screening period and,
4) Body weight >=15 kg

Participants are excluded from the study if any of the following criteria apply:
- Patients with nasal conditions/concomitant nasal diseases making them non-evaluable at Visit 1 or for the primary efficacy.
- Nasal cavity malignant tumor and benign tumors.
- Known of fungal invasion into sinus tissue.
- Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect the patient's participation in the study.
- Active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis unless documented adequately treated.
- Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection
- Known or suspected immunodeficiency
- 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.
- History of systemic hypersensitivity or anaphylaxis to dupilumab or any of its excipients.
- Treatment with commercially available dupilumab within 12 months, participation in prior dupilumab clinical trial, or discontinued dupilumab use due to adverse event.
- 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.
- Patients who are on intranasal corticosteroids (INCS) spray unless they have received stable dose for at least 4 weeks prior to Visit 1.
- Patients who have undergone sinus intranasal surgery (including polypectomy) within 6 months prior to Visit 1.
- Patients who have taken:
* Biologic therapy/systemic immunosuppressant to treat inflammatory disease or autoimmune disease within 5 half-lives prior to Visit 1
* Any investigational mAb within 5 half-lives prior to Visit 1
* Anti-IgE therapy (omalizumab) within 4 months prior to Visit 1.
- Treatment with a live (attenuated) vaccine within 4 weeks prior to Visit 1
- Leukotriene antagonists/modifiers unless patient is on a continuous treatment for at least 30 days prior to 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 screening or treatment period.
- Patients received SCS during screening period.
- Either intravenous immunoglobulin therapy and/or plasmapheresis within 30 days prior to Screening Visit (Visit 1).

Both

Allergic fungal rhinosinusitis

Drug: Dupilumab (SAR231893)
Pharmaceutical form:Injection solution, Route of administration: Subcutaneous

Drug: Placebo
Pharmaceutical form:Injection solution, Route of administration: Subcutaneous

1. Change from baseline in sinus opacifications assessed by computerized tomography (CT) scans using the Lund Mackay (LMK) score at Week 52 [ Time Frame: 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).

1. Change from baseline in sinus opacifications assessed by CT scans using the LMK score at Week 24 [ Time Frame: 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).

2. Proportion of patients who receive systemic corticosteroids (SCS) and/or undergo/plan to undergo surgery for AFRS during the planned study treatment period [ Time Frame: Baseline to Week 52 ]

3. Change from baseline in monthly average nasal congestion/obstruction score from the Nasal symptom Diary at Week 24 and Week 52 [ Time Frame: Baseline to Week 24 and Week 52 ]
The nasal congestion/obstruction scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms')

4. Change from Baseline in the monthly average anterior/posterior rhinorrhea score from the Nasal Symptom Diary at Week 24 and Week 52 [ Time Frame: Baseline to Week 24 and Week 52 ]
The rhinorrhea scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms').

5. Change from baseline in endoscopic NPS compared to placebo at Week 24 and Week 52 [ Time Frame: Baseline to Week 24 and Week 52 ]
The total nasal polyps score (NPS) is the sum of the right and left nostrils, ranging from 0 (no polyps) to 8 (large polyps causing complete obstruction).

6. Change from baseline in 22-item sino-nasal outcome test (SNOT-22) total score at Week 24 and Week 52 [ Time Frame: Baseline to Week 24 and Week 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.

7. Change from baseline in monthly average total symptom score (TSS) derived from the Nasal Symptom Diary at Week 24 and Week 52 [ Time Frame: Baseline to Week 24 and Week 52 ]
TSS ranges from 0 to 9. Higher scores on the TSS indicate greater symptom severity.

8. Change from baseline in visual analog scale (VAS) rhinosinusitis at Week 24 and Week 52 [ Time Frame: Baseline to Week 24 and Week 52 ]
VAS score ranges from 0 ('not troublesome') to 10 ('worst thinkable troublesome').

9. Change from baseline in University of Pennsylvania smell identification test (UPSIT) at Week 24 and Week 52 [ Time Frame: Baseline to Week 24 and Week 52 ]
The UPSIT score ranges from 0 to 40, with 40 being the best possible score.

10. Change from baseline in the score of decreased/loss of smell using the Nasal Symptom Diary at Week 24 and Week 52 [ Time Frame: Baseline to Week 24 and Week 52 ]
The decreased/loss of smell scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms').

11. Change from baseline to Week 52 in three Dimensional CT volumetric measurement of the paranasal sinuses [ Time Frame: Baseline to Week 52 ]

12. Incidence of treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) through Week 52 [ Time Frame: Baseline to Week 64 ]

13. Dupilumab concentration in serum over time [ Time Frame: Baseline to Week 52 ]

14. Percent change from baseline in total IgE in serum compared to placebo over the 52 weeks treatment period [ Time Frame: Baseline to Week 52 ]

15. Percent change from baseline in fungal-specific IgE in serum compared to placebo over the 52 weeks treatment period [ Time Frame: Baseline to Week 52 ]

16. Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time [ Time Frame: Baseline to Week 64 ]

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June. 21, 2021

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