E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Nasal polyposis (NP) is a chronic inflammatory disease of the nasal mucosa characterized by the presence of polyps in the upper nasal cavity. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028754 |
E.1.2 | Term | Nasal polyp |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of benralizumab vs placebo on the post-surgical recurrence of nasal polyps associated with worsening in CRSwNP (chronic rhinosinusitis with nasal polyposis) health status and/or clinical intervention |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of benralizumab vs placebo on:
- the post-surgical recurrence of nasal polyps
- CRSwNP (chronic rhinosinusitis with nasal polyposis) health status associated with post-surgical recurrence of nasal polyps
- changes in clinical interventions associated with post-surgical recurrence of nasal polyps
- SCS use for relief of NP symptoms and/or the need for additional surgery
- Nasal polyposis-associated symptoms
- sense of smell
- general HRQoL (Health-related quality of life)
- sinus opacification (Lund-Mackay Score)
Safety objectives:
- To assess the safety and tolerability of benralizumab
- To assess the pharmacokinetics and immunogenicity of benralizumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Participants with bilateral sinonasal polyposis, and prior use of SCS (unless a medical contraindication) and ESS within 3 years, who have severity consistent with a need for surgery as described by:
(a) A minimum total NPS of 4 out of a maximum score of 8 (with a unilateral score of at least 1 for each nostril) at V1 as determined by the study imaging core lab,
(b) Ongoing symptoms for at least 12 weeks prior to V1 (question 11 of NPSQ);
(c) Sinonasal symptom (SNOT-22) total score ≥ 30 at enrolment (V1)
Participant must meet the following criteria at the randomisation visit (V3):
- Completion of surgical procedures consistent with those described in the Pre randomisation Surgical Guideline
- Successful surgical polyp removal as evidenced by no visible polyps, confirmed by the Investigator
- SNOT-22 improvement greater than or equal to the MCID of 8.9 compared to the assessment prior to surgery |
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E.4 | Principal exclusion criteria |
- Participants with conditions or concomitant disease that makes them non-evaluable for the efficacy endpoint such as:
(a) Unilateral antrochoanal polyps
(b) Nasal septal deviation that occludes at least one nostril so as to prevent NPS scoring
(c) Current rhinitis medicamentosa
(d) Allergic fungal rhinosinusitis or allergic fungal sinusitis
(e) Nasal cavity tumours
- Clinically important comorbidities that could confound interpretation of clinical efficacy results including, but not limited to: active upper or lower respiratory tract infection, cystic fibrosis, primary ciliary dyskinesia, eosinophilic diseases other than asthma (eg, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic granulomatosis with polyangitis [Churg-Strauss syndrome], hypereosinophilic syndromes), granulomatosis with polyangitis (Wegener's granulomatosis), Young’s syndrome, etc.
- Participants experiencing an asthma exacerbation requiring systemic (oral and/or parenteral) corticosteroids treatment or hospitalisation (> 24 hrs) for treatment of asthma within 4 weeks prior to V1.
- Participants should not be randomised in case of persistent or new post-surgical infection (eg, fever or nasal muco-purulent discharge), uncontrolled pain, acute sinusitis, nasal infection, or upper respiratory infection in the 2 weeks before randomisation
- History of anaphylaxis to any biologic therapy or vaccine.
- A helminth parasitic infection diagnosed within 24 weeks prior to the date of informed consent and has not been treated with, or has failed to respond to standard of care therapy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time from randomisation to the earliest recurrence of nasal polyps associated with SNOT-22 worsening and/or a clinical intervention.
- Recurrence of nasal polyps will be determined by an NPS showing an increase ≥ 1 from that recorded at baseline
- SNOT-22 worsening is defined as a clinically meaningful deterioration in SNOT-22 compared to baseline (worsening ≥ 8.9 [MCID - Minimum clinically importance difference])
- Clinical intervention is defined as a need for NP surgery, SCS use for NP, or need for a biologic. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
through the end of the treatment period |
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E.5.2 | Secondary end point(s) |
- Time from randomisation to the earliest post-baseline timepoint with an increase in NPS compared to baseline (increase ≥ 1), which is confirmed at the next assessment at least 4 weeks later (key secondary)
- Time from randomisation to the earliest post-baseline timepoint with a clinically meaningful deterioration in SNOT-22 compared to baseline (worsening ≥ 8.9 [MCID] [Minimum clinically importance difference]), which is confirmed at the next assessment at least 4 weeks later (key secondary)
- Change from baseline in SNOT-22 [SinoNasal Outcome Test 22 item]
- Time from randomisation to the first clinical intervention (need for NP surgery, SCS , need for a biologic) due to nasal polyps recurrence (key secondary)
- Time from randomisation to first SCS burst for NP
- Time from randomisation to need for subsequent nasal surgery
- Change from baseline in the NPSQ [Nasal polyposis symptoms questionnaire]
- Change from baseline in DSS [Difficulty with sense of smell]
- Change from baseline in the UPSIT [University of Pennsylvania Smell Identification Test]
- Change from baseline in the SF-36v2 [Short Form 36-item Health survey, Version 2]
- Change from baseline in Lund Mackay score and sinus severity score by Quantitative CT analysis
- AEs, vital signs, and clinical laboratory values
- Assessments related to AEs [adverse events] cover
- Vital signs parameters include systolic and diastolic blood pressure, and pulse, as well as respiration rate and body temperature. Assessments related to vital signs cover: observed value, absolute and percent change from baseline values over time
- Serum PK
- Benralizumab ADA |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
through the end of the treatment period |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Canada |
Denmark |
Germany |
Hungary |
Poland |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study will occur when the required number of primary and key secondary endpoint events have been observed. Participants will be followed for a minimum of 56-week double-blind treatment, up to a maximum of 104 weeks in order to accrue an adequate number of events for the primary endpoint and the key secondary endpoint. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial days | 10 |