Study protocol: the biologics in severe chronic rhinosinusitis with nasal polyps survey

Inclusion criteria

Patients over 18 years old requiring biologics for CRSwNP in accordance with its marketing approval in France (ie, severe nasal polyposis, with lack of control under nasal corticosteroid, systemic corticosteroids and surgery) are invited to participate in BIOPOSE.

Exclusion criteria

Patients are excluded in case of:

• Systemic corticosteroid medication during the 4 past weeks

• Biological treatment with anti-IgE (omalizumab), anti-IL-5/IL-5R (mepolizumab, benralizumab) or anti-IL-4/IL-13R (dupilumab) or any other biotherapy for inflammatory diseases in the previous 6 months apart from ongoing biotherapies for severe asthma

• Hypersensitivity to humanised antibodies

• Documented SARS-Cov2 infection in the last 3 months with persistent olfactory disorders related to COVID

• Pregnant or breastfeeding women

• Patient without social coverage

Participating centres

Patient recruitment has started at the following centres:

• University Hospital of Lille, France

• University Hospital Bicêtre Paris-Sud, France

• University Hospital of Bordeaux, France

• University Hospital of Clermont-Ferrand, France

• Centre Hospitalier Intercommunal Creteil and University Hospital Henri Mondor, France

• University Hospital of Lariboisière, Paris, France

• University Hospital of Nancy, France

• University Hospital of Nantes, France

• La Conception University Hospital, Marseille, France

• University Hospital of Toulouse, France

• University Hospital of Nice, France

• University Hospital of Montpellier, France

• University Hospital of Lyon, France

• University Hospital of Poitiers, France

• Institut Arthur Vernes, Paris, France

The laboratory centre for an ancillary biological study is:

After the establishment of the study in these initial BIOPOSE clinics, we will invite more centres to join the study and begin patient recruitment.

Patient identification and recruitment

Eligible patients are identified and invited to participate in the study. They receive all study information from the local recruitment centre. Patients are recruited during a clinical follow-up visit. There might be small variations in recruitment and data collection between participating centres due to the clinical routine of each centre.

Clinical assessments

Eligible patients are followed regularly in each participating centre. The first visit (V0) corresponds to the inclusion and prescription of the biologics. V1 and V2 are planned every 3 months, and then patients will be followed every 6 months until completion of the study. At each visit, patients undergo a complete sinonasal examination using rigid or flexible fibreoptic endoscope. Patients will not be subjected to additional invasive measurements solely for the purposes of the study; examinations and tests are only done if clinically indicated or as part of the local follow-up protocol. All examinations and tests are performed following the local standard operating procedures of the clinic.

SNOT-22

SNOT-22 is a patient self-administered dedicated chronic sinusitis QoL questionnaire used to follow the outcomes of medical and surgical endoscopic endonasal procedures.1 40 42 SNOT-22 comprises 22 items grouped into 5 domains: rhinologic symptoms, extranasal rhinologic symptoms, ear/facial symptoms, psychological dysfunction and sleep disfunction.43 Each item is scored from 0 (no problem) to 5 (problem as bad as it can be) with 2-week recall, resulting in a total score ranging from 0 to 110 points. The minimal clinically important difference (MCID) value is set at 8.9 points.44 It has been translated and validated into French language.45 This questionnaire is fulfilled by the patient at each visit.

Asthma control test

Asthma control test (ACT) is a patient self-administrated questionnaire dedicated to asthma control.46 It comprises five items scored from 1 (not controlled) to 5 (completely controlled), with a 4-week recall. The scores range from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score >19 indicates well-controlled asthma. ACT is fulfilled by all patients with comorbid asthma at each visit.

Nasal polyp score

Nasal endoscopy is performed to determine the NPS,27 rated for each side as follow: 0, no polyp; 1, polyp remaining in the superior part of the middle meatus; 2, polyps extended to the inferior part of the middle turbinate but without extension below the superior third of the inferior turbinate; 3, polyps extended to the level of the inferior turbinate, without reaching its inferior third; and 4, polyps leading to a complete obstruction of the nasal fossa. The total NPS ranges from 0 to 8 points.

Lund-Mackay score

Lund-Mackay score (LMS) is a staging system radiologic score, based on sinus opacity on CT scan examination,47 with a good interobserver reliability.48 This score ranges from 0 (complete lucency of all sinuses) to 24 (complete opacity of all sinuses) and is interesting to predict CRSwNP severity in association with SNOT-22.49

Symptoms scores

To assess the impact of the main symptoms of CRSwNP, 0–100 visual analogue scales of nasal blockage, rhinorrhea, facial pain and global symptoms will be recorded.50–52 The nasal congestion score, used in most of biologics phase III studies,26–28 ranges the nasal congestion symptom from 0 to 3. Smell loss will be assessed using a visual analogical scale (VAS), and all centres are not equipped with olfactory testing tools.

ENT examinations

The ears, nose and throat (ENT) examinations performed in the participating centres include nasal endoscopy (either rigid or flexible) to record the NPS as described above: nasal congestion score (0–3) and VAS for each nasal symptom (0–10) at each visit—nasal obstruction, smell lost, rhinorrhea, craniofacial pain are recorded. Topical medication used (nasal corticosteroids and/or nasal rinses), the use of systemic corticosteroids (number of courses) and other past treatments (macrolides or else) are also recorded. Type and timing of past surgical procedures and/or time to surgery after introduction of biologics are collected. The biologics used, molecule, dose, duration, adverse events and reason for stopping (if required), are recorded as well as the therapeutic strategy for biologics prescription, including switching of biologics. A general physician and a dermatologist can request any extra follow-up visit to help us monitor the side effects. The choice of biologics prescribed is not randomised at inclusion. While respecting the scope of the molecule’s authorisation and the criteria for reimbursement in France, the decision to treat, the choice of biologics, the methods of administration and the duration of treatment are left to the discretion of the physician managing the patient. Patients whose biologics prescribed at inclusion is discontinued or modified during the standardised 18-month follow-up period continue to be monitored according to the monitoring schedule (M0, M3, M6, M12 and M18). During this follow-up period, the need for surgery and/or systemic steroids will follow the French ENT Society guidelines regarding CRSwNP.21 Therefore, patients will undergo surgery or a course of systemic steroids while under biologics in case of uncontrolled severe disease based on nasal symptoms and the impact on their QoL. Blood samples are performed at initial visit, M3, M6, M12 and M18 to look for T2 inflammation biomarkers (blood eosinophilic count and total IgE concentration). Indeed, several studies have shown that CRSwNP is associated with a T2 immune response leading to B cell release of IgE, mucosal recruitment of eosinophils from bone marrow via IL-5-mediated, IL-4-mediated and IL-13-mediated chemoattractant production.24 53 54 Sinus imaging is performed at 6 months, and the LMS is assessed.

Other data from clinical records

At recruitment, baseline medical information and comorbidities (atopic disease, asthma, aspirin intolerance, sulfite intolerance, chronic otitis media, obstructive sleep apnea, gastro-oesophageal reflux disease and other significative comorbidities) are collected from clinical records. In comorbid asthma patients, ACT, Global Initiative for Asthma 2021 medication status and the number of exacerbation/hospitalisation/resuscitation for asthma in the past year will be collected.

Information on questionnaires

Participating patients are asked to complete the SNOT-22 questionnaire at every visit and the ACT in case of comorbid asthma as described above.

Study power and sample size

We expect to recruit at least 300 patients in BIOPOSE, but our task is to expand recruitment beyond 300 patients and establish a permanent and nationwide cohort. Indeed, after the establishment of the cohort, it will be possible for more centres to join and contribute to patients, resulting in a higher cohort. The main aim of the study is to estimate the evolution of patients’ QoL using the SNOT-22 score at 24 weeks of treatment. The primary endpoint is the frequency of patients improving their QoL, improvement being defined as a change in QoL between baseline and 24 weeks greater than the MCID in absolute value (8.9).44 The number needed to treat is based on literature and the proportion of patients improved estimated. In the two Phase III trials evaluating omalizumab in CRSwNP (POLYP 1 and POLYP 2),27 69 and 58 patients, respectively, in the omalizumab arm had completed the study protocol. The change in SNOT-22 score at 24 weeks of treatment was −24.70 (±2.01) and −21.59 (±2.25), respectively (± SEM), that is, SD of 16.7 and 17.3, respectively, exceeding the accepted threshold of MCID (8.9, 30). In the two Phase III trials evaluating dupilumab in CRSwNP (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52),26 124 and 282 patients, respectively, in the dupilumab arm had completed the study protocol. The change in SNOT-22 score at 24 weeks of treatment was −30.43 (±1.54) and −27.77 (± 1.26), respectively (± SEM), that is, SD of 14.0 and 21.1, respectively, again exceeding the MCID.38 Based on these data, and assuming a Gaussian distribution for variation in QoL, we estimate improvement frequencies of 83%, 77%, 94% and 81% for these four trials. We assumed an expected frequency of 80%. We set the relative precision at 10% or 8% in absolute terms (precision is defined by the half-width of the 95% CI). Under these assumptions, 100 patients will be required. Given the latest arrival of mepolizumab, 1 year after dupilumab in France, we seek to recruit 300 patients to have a representation of the two biologics in the database. The parameters of randomisation and blinding do not apply to our cohort study describing patients treated with the same therapeutic modality. Selection bias is reduced by compliance with the authorisation for biologics. Measurement bias is limited by the prospective nature of the analysis. Information bias is prevented by the choice of a French-validated QoL questionnaire (SNOT-22) as the primary endpoint, for which the MCID has been established in the literature.