Baseline disease characteristics among patients with chronic rhinosinusitis with nasal polyps in AROMA: A global registry study

Abstract

Background:

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease of the nasal and paranasal sinuses. In phase III clinical trials, dupilumab significantly improved objective and patient-reported measures of CRSwNP versus placebo. However, a real-world evidence gap exists between efficacy and effectiveness data for dupilumab in CRSwNP, particularly in the United States.

Objective:

Assessing Long-teRm Outcomes of dupiluMAb Treatment in Adult Patients With CRSwNP (AROMA) aims to characterize patients who receive dupilumab for CRSwNP in a real-world setting and evaluate long-term effectiveness.

Methods:

AROMA is a prospective global registry study that is recruiting adult patients with uncontrolled CRSwNP who were initiating dupilumab and following them for up to 36 months. Baseline demographics and disease characteristics were assessed for all patients entering the registry.

Results:

As of February 2023, the study had recruited 303 patients of a target enrollment of 700, with a mean age of 50.8 years, and 57.1% were recruited in the United States. A history of asthma was reported in 70.6% of the patients and a history of allergic rhinitis in 70.6% of the patients. In the 24 months before enrollment, 61.7% of the patients had at least one sinonasal surgery and 68.6% used systemic corticosteroids. At baseline, 35.0% of the patients were receiving intranasal corticosteroids and 33.3% were receiving leukotriene receptor antagonists. In the Global Patient Assessment, 31.7% and 29.7% of the patients reported moderate and severe CRSwNP symptoms, respectively, during the past week.

Conclusion:

Patients in AROMA had a high disease burden in terms of symptoms, comorbidities, and treatment burden. Nearly two-thirds of patients with CRSwNP had at least one sinonasal surgery before initiating dupilumab.

Clinical trial NCT04959448 (AROMA), www.clinicaltrials.gov

PLAIN LANGUAGE SUMMARY (PLS)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a condition that causes partial or complete blockage of the nose, which makes it difficult to breathe. This has a negative effect on many aspects of a person’s life, and a person with severe disease is more likely to be affected by similar diseases, e.g., asthma. In addition, people with severe CRSwNP often find the benefits of treatment temporary, with polyps in their nose regrowing after surgery to remove them. A drug called dupilumab, which is injected under the skin every other week, has been approved for treating people with CRSwNP. This article presents initial findings from a large study called Assessing Long-teRm Outcomes of dupiluMAb Treatment in Adult Patients With CRSwNP (AROMA) of people with severe CRSwNP who were monitored for 3 years after beginning dupilumab treatment, reporting the average characteristics of patients before they began dupilumab treatment. The paper found that many people with CRSwNP also had asthma and allergic rhinitis, and they took multiple courses of steroids in the year before starting dupilumab.

INTRODUCTION

Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with a high symptom burden and significant reduction in health-related quality of life (HRQoL), particularly in patients with moderate-to-severe disease.^1,2 An estimated 1–4% of the adult population in Europe and in the United States have CRSwNP. Of these patients, up to three-fourths have a coexisting type 2 inflammatory disease such as asthma (5–56%), nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) (∼16%), and allergic rhinitis (17–76%).^3,4

First-line therapies for treating CRSwNP include intranasal corticosteroids (INCS) and saline solution irrigations. If inadequate disease control persists, short-term oral corticosteroids are recommended by the European Position Paper on Rhinosinusitis and Nasal Polyps 2020.¹ Short courses of systemic corticosteroids are advised only for patients with uncontrolled CRSwNP. Endoscopic sinus surgery is recommended for patients who are refractory to primary medical therapy.¹ However, there are several challenges associated with CRSwNP management. Long-term steroid use is associated with an increased risk of adverse events and is not recommended.¹

For the treatment of uncontrolled or severe CRSwNP, biologics have demonstrated efficacy in randomized clinical trials (RCTs).^5–8 Biologics such as dupilumab target the underlying type 2 inflammation mechanisms or processes associated with CRSwNP. Dupilumab inhibits interleukin (IL)-4 and IL-13 signaling by binding to the IL-4 receptor α subunit shared by the IL-4 and IL-13 receptor complexes. Inflammation driven by IL-4 and IL-13 is an important component in the pathogenesis of CRSwNP. In the phase III LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 trials,⁶ dupilumab significantly improved objective and patient-reported outcome measures in patients with uncontrolled CRSwNP.

Although RCT data are considered the criterion standard for assessing the clinical efficacy of new therapies, real-world evidence represents the full spectrum of therapeutic practices in a more heterogeneous patient population.^9,10 There is an evidence gap between dupilumab efficacy observed over 52 weeks in RCTs and dupilumab’s long-term real-world effectiveness, particularly in the United States and in patients with uncontrolled CRSwNP. Real-world cohort studies in Italy¹¹ and the Netherlands¹² have been conducted, although the follow-up duration was similar to the phase III trials.

The primary aims of the AROMA study are to collect data on the long-term effectiveness of dupilumab through assessment of patient-reported symptoms and HRQoL related to CRSwNP and other type 2 comorbidities, and to characterize patients who receive dupilumab for CRSwNP in a real-world setting with respect to their medical history and demographic and disease characteristics. AROMA is the first global registry study for patients with CRSwNP and will provide insights into patient profiles and treatment patterns in different regions where dupilumab is approved. This article reports the baseline characteristics of the first 303 patients enrolled in AROMA.

METHODS

Study Design and Patient Population

AROMA is a phase IV, prospective, observational, multicenter registry study being conducted in the United States, Canada, Germany, Italy, Japan, and the Netherlands. Details of the study design have been reported previously (Fig. 1).¹³ In brief, the target enrollment for the study is 700 adult patients with uncontrolled CRSwNP who are initiating dupilumab. The study will follow up these patients for up to 36 months. Because this is a registry, there are no restrictions on dupilumab dosage or concomitant medication during the study. The study duration for each participant is up to 36 months, with study visits beginning at baseline and scheduled every 3 months through month 24, and then every 6 months through to the planned end of the study at month 36. This study protocol was reviewed and approved by Advarra, a commercial institutional review board (approval Pro00054731), and all the patients provided written informed consent before enrollment and any study-related procedure.

Figure 1.

AROMA study design. Outcomes recorded included measures for CRSwNP (LMK-CT, PNIF, Sniffin Stick Test, spirometry, UPSIT, AR-VAS, LoS, NC, TSS, SNOT-22), asthma (ACQ-6, FeNO, mini-AQLQ), eczema/dermatitis (POEM), quality of life (mini-RQLQ[S], EQ-5D-5L, SF-12), productivity/activity (WPAI-CRSwNP), and health-care resource use (HCRUQ). Full details have been reported previously (Ref. 13). AROMA = Assessing Long-teRm Outcomes of dupiluMAb Treatment in Adult Patients With CRSwNP; CRSwNP = chronic rhinosinusitis with nasal polyps; LMK-CT = Lund–Mackay computed tomography; PNIF = peak nasal inspiratory flow; UPSIT = University of Pennsylvania Smell Identification Test; AR-VAS = Allergic Rhinitis Visual Analog Scale; LoS = loss of smell; NC = nasal congestion; TSS = total symptom score; SNOT-22 = 22-item Sino-Nasal Outcome Test; ACQ-6 = 6-item Asthma Control Questionnaire; FeNO = fractional exhaled nitric oxide; mini-AQLQ = Mini Asthma Quality of Life Questionnaire; POEM = Patient-Oriented Eczema Measure; mini-RQLQ(S) = Mini Standardized Rhinoconjunctivitis Quality of Life Questionnaire for patients ≥ 12 years of age; EQ-5D-5L = European Quality of Life 5-Dimensions, 5-Level Questionnaire; SF-12 = 12-item Short-Form; WPAI-CRSwNP = Work Productivity and Activity Impairment Questionnaire for CRSwNP; HCRUQ = Healthcare Resource Utilization Questionnaire; IgE = immunoglobulin E.

Assessments

Baseline assessments of patients include demographics, disease characteristics, medical history, the presence of type 2 comorbidities, and health-care resource use, i.e., otolaryngologist and allergist visits. Measures of dupilumab effectiveness are assessed at baseline and at study visits until month 36. The 22-item Sino-Nasal Outcome Test (SNOT-22), the Work Productivity and Activity Impairment Questionnaire for CRSwNP, and the 12-item Short-Form will be assessed at baseline, every 3 months for the first 2 years, and every 6 months in the last year of the study. Other measures of dupilumab effectiveness assessed include the total symptom score, nasal congestion, loss of smell, University of Pennsylvania Smell Identification Test (UPSIT; Sensonics International, Haddon Heights, NJ, USA), and Lund–Mackay computed tomography score. The secondary outcomes of the Global Impression for Symptom Severity – Treatment Satisfaction (Global Patient Assessment) will be assessed at baseline, every 3 months in the first 2 years, and every 6 months in the last year of the study, and the Global Impression for Disease Severity (Global Physician Assessment) will be assessed at baseline and every 6 months.

Statistical Analysis

Formal statistical analyses were not conducted. The results for symptoms, HRQoL, and health-care resource use by surgery history are summarized descriptively.

RESULTS

Baseline Characteristics

As of February 2023, the study had recruited 303 patients. Of those, 173 (57.1%) were recruited from the United States, 68 (22.4%) from Italy, 50 (16.5%) from Japan, 9 (3.0%) from Canada, 2 (0.7%) from Germany, and 1 (0.3%) from the Netherlands. The mean age was 50.8 years, and there was an equal distribution by gender (49.5% male) (Table 1). Among the countries with the most enrolled patients (the United States, Italy, and Japan), differences in baseline demographics (age, gender, race) and medical history were observed (Supplemental Table 1).

Table 1.

Patient demographics and disease characteristics (N = 303)

SD = standard deviation; BMI = body mass index; NSAID-ERD = nonsteroidal anti-inflammatory drug-exacerbated respiratory disease; SCS = systemic corticosteroids; CRSwNP = chronic rhinosinusitis with nasal polyps.

Biomarkers

At enrollment, 79 patients (26.1%) had a mean ± standard deviation (SD) eosinophil count of 0.5 ± 0.86 10⁹/L and 52 patients (17.2%) had a mean ± SD immunoglobulin E count of 209.2 ± 178.8 kU/L.

Coexisting Type 2 Inflammatory Conditions

Many patients with CRSwNP in AROMA had coexisting type 2 inflammatory conditions, and 94.1% reported one or more type 2 conditions at screening. A history of asthma was reported in 70.6% of patients in AROMA, a history of allergic rhinitis in 70.6%, and 25.7% reported a history of NSAID-ERD. Other allergic conditions are listed in Table 1.

Surgical History

Although a large proportion of patients had received previous sinonasal surgery, more than one-third of patients received no surgery before initiating dupilumab. In the 24 months before enrollment, 187 patients (61.7%) had at least one sinonasal surgery and 116 (38.3%) were surgery naive (Table 1). Of the patients in AROMA, 118 (38.9%) had one previous surgery, 27 (8.9%) had two previous surgeries, and 69 (22.8%) had two or more previous surgeries. The mean ± SD number of previous surgeries was 1.9 ± 1.73.

Systemic Corticosteroid/Oral Corticosteroid Use

At enrollment, 208 patients (68.6%) reported systemic corticosteroid use for CRSwNP in the previous 24 months (Table 1). The most prescribed corticosteroids, with an end date within 3 months before screening, were prednisone (n = 65), methylprednisolone (n = 14), and prednisolone (n = 12) (Table 2). In the 12 months before enrollment, the most commonly prescribed corticosteroids were prednisone (n = 103), prednisolone (n = 28), and methylprednisolone (n = 26) (Table 3).

Table 2.

Previous and concomitant medications in the 3 months before enrollment (N = 303)

OCS = oral corticosteroids; SCS = systemic corticosteroids; INCS = intranasal corticosteroids; LTRA = leukotriene receptor antagonist.

Table 3.

OCS and/or SCS most frequently used (n > 2) in the 12 months before enrollment

OCS = oral corticosteroids; SCS = systemic corticosteroids; SD = standard deviation.

The patients were also receiving various other treatments for CRSwNP at baseline. Use of INCS was reported by 35.0% of the patients, 33.3% reported use of a leukotriene receptor antagonist, and 1.3% reported use of biologics. In addition, 45.2% of the patients received a prescription for antibiotics for CRSwNP in the 24 months before enrollment.

Disease Burden

At baseline, the patients in AROMA reported a moderate-to-high disease burden (Table 4). The mean ± SD baseline scores were total symptom score, 5.4 ± 2.29; nasal congestion, 1.8 ± 0.89; loss of smell, 2.2 ± 1.09; UPSIT, 15.0 ± 12.61; 22-item Sino-Nasal Outcome Test, 45.4 ± 22.17; Lund–Mackay computed tomography, 15.7 ± 5.94; and EuroQol-Visual Analog Scale, 72.1 ± 19.90. In the baseline Global Patient Assessment, 31.7% and 29.7% of the patients reported moderate or severe CRSwNP symptoms, respectively, during the past week. In the Global Physician Assessment, 13.2%, 44.6%, and 16.5% of the patients were rated as having moderate, severe, and very severe CRSwNP symptoms, respectively (Fig. 2).

Table 4.

Baseline disease burden and clinical parameters in the study population

SD = standard deviation; SNOT-22 = 22-item Sino-Nasal Outcome Test; UPSIT = University of Pennsylvania Smell Identification Test; LMK-CT = Lund–Mackay computed tomography; EQ-VAS = EuroQol-Visual Analog Scale; FeNO = fractional exhaled nitric oxide.

*Lower scores indicate greater disease severity.

Figure 2.

CRSwNP disease symptoms assessed by the patient and the physician at baseline (N = 303).* CRSwNP = chronic rhinosinusitis with nasal polyps. *“Very severe symptoms” was not available as a category in the Global Patient Assessment questionnaire; “No symptoms” was not available as a category in the Global Physician Assessment.

Disease Burden by Patient Specialty Care (U.S. Cohort)

Of the patients in the U.S. cohort, 115 received care from both ear, nose, and throat specialists and 131 from allergists. Among the U.S. patients who received specialty care, patient demographics across specialties were similar (mean age range 49.3–49.4 years, 42–43% male, 76–80% White) (Supplemental Table 2). There were minimal differences in disease burden between specialties (Table 5). The pattern of clinical assessment was similar regardless of the specialty care practitioners seen: 89–91% of the patients were assessed for disease activity measures (Table 5). Regardless of specialty, other assessments before enrollment were infrequent, including UPSIT (26–31% of patients), computed tomographies (8–9%), and biomarkers (eosinophils, 10–12%; immunoglobulin E, 12–14%).

Table 5.

Baseline disease scores by prescriber specialty in the U.S. cohort

ENT = ear, nose, and throat; SD = standard deviation; SNOT-22 = 22-item Sino-Nasal Outcome Test; UPSIT = University of Pennsylvania Smell Identification Test; LMK-CT = Lund–Mackay computed tomography.

*Patients could be counted in >1 group.

#Lower scores indicate greater disease severity.

DISCUSSION

AROMA is the first prospective, observational, global registry study to characterize patients with CRSwNP who are initiating dupilumab treatment in a real-world setting, with a primary objective of capturing effectiveness and safety data that cover dupilumab treatment for up to 36 months. In this interim analysis of baseline characteristics in the AROMA global registry, adult patients with CRSwNP initiating dupilumab in a real-world setting had a high burden of systemic treatments and coexisting type 2 inflammatory diseases, especially asthma and allergic rhinitis (Fig. 3).

Figure 3.

Summary of findings.

In comparison with the SINUS-24 and SINUS-52 studies,⁶ patients in AROMA were slightly younger (mean age 52 years versus 50.8 years), and the ratio of men to women was closer to parity (49.5% and 51.5% versus 60.0% and 40.0%, respectively). Most patients (61.4%) reported their disease as moderate or severe at baseline. The initial disease burden for the patients in the AROMA registry was comparable with that of the patient population in the SINUS-24 and SINUS-52 phase III studies,⁶ and reflected the high prevalence of coexisting type 2 inflammatory diseases and the heterogeneous nature of the real-world population of patients with CRSwNP. Other studies have estimated the prevalence of coexisting asthma and NSAID-ERD in patients with CRSwNP as up to 65% and 16%, respectively,^4,14–16 although the rates are likely higher among the patients with severe CRSwNP. In the U.S. cohort, the high burden of disease at baseline was seen, regardless of the type of specialist care, with many patients consulting both ENTs and allergists. Patterns of care by different specialties in patients with CRSwNP may lead to assumptions about the disease characteristics of the patients treated by each specialty, which may inform divergent real-world treatment approaches.

Patients who entered the study had low baseline use of INCS compared with other studies (35.0% versus 85.0% INCS adherence in the phase IV Dupilumab in the Treatment of Severe Uncontrolled CRSwNP: a Multicentre Observational Real-life Study (DUPIREAL) study).¹¹ INCS, nasal irrigation, and short-term corticosteroids are recommended as first-line therapies for patients with CRSwNP in the current clinical guidelines, with biologics considered an add-on therapy.¹ However, ENTs estimate that INCS adherence is often as low as 50% in real-world patients with CRSwNP, despite its importance as a first-line therapy.¹⁷ Because the patients in AROMA only listed INCS medications ongoing at baseline, it is possible that more study patients were using INCS but discontinued before enrollment. Patients commonly cite safety concerns associated with chronic steroid use and lack of symptom improvement as reasons for nonadherence to their INCS regimens.

Approximately two-thirds of patients (61.7%) had undergone one or more surgeries for CRSwNP before initiating dupilumab, a similar rate to the SINUS-24 and SINUS-52 population (63%).⁶ However, a significant proportion of patients had no previous surgery before initiating dupilumab, even though biologics are currently recommended for patients with uncontrolled CRSwNP after standard-of-care therapies and/or surgery.¹ It is possible that these patients were deemed ineligible candidates for surgery (e.g., the presence of severe comorbidities) or they declined treatment.

Real-world data from AROMA will provide additional insight into the effectiveness of dupilumab in these patient populations and inform future treatment practices based on patient adherence to concomitant medications as well as treatment preferences (e.g., the avoidance of sinonasal surgery).

One of the main challenges of real-world evidence studies is missing data or inconsistent data collection, which can negatively affect the analysis and conclusions drawn. Due to missing patient responses, the prevalence of type 2 comorbidities and overall treatment burden might be underreported in AROMA. Despite these limitations, analysis of the interim data from AROMA shows that patients receiving dupilumab in real-world conditions have similar demographics and disease burden at enrollment compared with patients in the phase III RCTs.⁶

CONCLUSION

This planned interim analysis of AROMA confirms that patients with CRSwNP in a real-world setting have a high disease burden in terms of coexisting diseases, overall symptoms, and treatment burden. Previous use of INCS was low, and only two-thirds of the patients with CRSwNP had at least one sinonasal surgery before starting dupilumab treatment, which suggests that real-world treatment practices differ from clinical guidelines, and more insight into patient treatment adherence may be required.