Evaluation of LYR-210 and Dexamethasone in Adults with Chronic Rhinosinusitis Without Nasal Polyps: A Randomized, Blinded, Controlled Phase III Trial

The primary objective of this study is to evaluate the **efficacy** of LYR-210, compared with a sham procedure control, in improving the three cardinal symptoms of **Chronic Rhinosinusitis (CRS)** in adult participants without nasal polyps, who have previously failed medical management. This is clinically relevant as it addresses the need for effective treatment options for patients with CRS who do not respond to standard medical therapies, potentially improving their quality of life and reducing disease burden.

Secondary objectives include:

• Evaluating the efficacy of LYR-210, compared with a sham procedure, in improving the three cardinal symptoms of CRS in participants without nasal polyps or with nasal polyps of grade 1, who have previously failed medical management.
• Assessing the efficacy of LYR-210, compared with sham control, in improving individual CRS symptoms, CRS-related quality of life, the extent of inflammation in the ethmoid sinuses, and the need for rescue treatment in participants without nasal polyps or with nasal polyps of grade 1, who have previously failed medical management.

The clinical trial involves a total of **90 participants** diagnosed with **Chronic Rhinosinusitis (CRS) in Adults**. The study population includes both male and female subjects aged 18 years and older, who have been diagnosed with CRS without nasal polyps and have previously failed medical management. Participants were selected based on specific criteria, including a confirmed bilateral ethmoid disease on computed tomography and a mean 3 cardinal symptom score. The trial population is characterized by individuals who have undergone at least two trials of medical treatments in the past. Participants are required to comply with all study requirements and have provided written informed consent. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.

The clinical trial is designed to evaluate the efficacy and safety of the **LYR-210 System** for the treatment of **chronic rhinosinusitis** (CRS) in adults. This is a Phase III, randomized, double-blind, controlled, parallel-group trial. The primary objective is to assess the improvement in the three cardinal symptoms of CRS in participants without nasal polyps who have previously failed medical management. The trial is expected to conclude by April 2025, with recruitment having commenced in August 2022.

Participants will be randomly assigned to receive either the LYR-210 System or a sham procedure. The trial will involve several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), a diagnosis of CRS, and bilateral ethmoid disease confirmed via computed tomography. Participants must have undergone at least two trials of medical treatments in the past and agree to comply with all study requirements, including the cancellation of any preplanned elective sinonasal surgery for the study's duration.

Following the screening visit, participants will attend regular follow-up visits to monitor their progress and assess the primary endpoint, which is the change from baseline in the 7-day average composite score of the three cardinal symptoms at Week 24. Secondary endpoints include changes in individual symptom scores, the Sino-Nasal Outcome Test (SNOT-22) total score, and the percent opacification of the bilateral anterior and posterior ethmoids as determined by 3-D volumetric CT analysis at Week 20. The end-of-study visit will mark the conclusion of the participant's involvement, which is expected to last up to 24 weeks.

Participants may be withdrawn from the study early if they fail to comply with study requirements, experience adverse events that necessitate discontinuation, or choose to withdraw consent. The trial's design ensures that all procedures are conducted in a manner that maintains the integrity of the data and the safety of the participants.

The clinical trial involves the use of two primary treatments. The first treatment is **DEXAMETHASONE**, which is administered in the form of a tablet. The active substance, dexamethasone, is of chemical origin. The dosage is set at a maximum daily dose of 10 mg, with the same amount being the maximum total dose. The route of administration is oral, and the treatment period is limited to a maximum of 1 day. Participant compliance with the dosing schedule will be monitored to ensure adherence to the protocol.

The second treatment is the **LYR-210 System**, which contains the active substance **MOMETASONE FUROATE**. This treatment is provided as a powder for inhalation and is intended for intranasal use. The maximum daily dose is 89 µg, with a total maximum dose of 15,000 µg over the course of the treatment. The maximum treatment period for the LYR-210 System is 24 weeks. The LYR-210 System is a product of LYRA THERAPEUTICS, INC. and is used in conjunction with a device that does not have a CE mark. Compliance with the administration schedule will be closely monitored to ensure the efficacy and safety of the treatment.

In this trial, the LYR-210 System is compared against a sham procedure control to evaluate its efficacy in treating chronic rhinosinusitis (CRS) in adults without nasal polyps who have previously failed medical management. The trial is designed to assess the improvement in the three cardinal symptoms of CRS. No additional non-experimental treatments, such as standard-of-care therapy or placebo, are specified in the trial protocol.

The efficacy of the LYR-210 System in the treatment of **Chronic Rhinosinusitis (CRS)** will be assessed through a Phase III, randomized, blinded, controlled, parallel-group clinical trial. The primary objective is to evaluate the efficacy of LYR-210 compared to a sham procedure control in improving the three cardinal symptoms of CRS in participants without nasal polyps who have previously failed medical management. The primary endpoint is the change from baseline in the 7-day average composite score of the three cardinal symptoms: nasal blockage/obstruction/congestion, facial pain/pressure, and anterior/posterior nasal discharge at Week 24.

Secondary endpoints include the change from baseline in the 7-day average composite score of the three cardinal symptoms at Week 24, as well as individual scores for nasal blockage/obstruction/congestion, anterior/posterior nasal discharge, and facial pain/pressure. Additional secondary endpoints involve the change from baseline in the 22-item Sino-Nasal Outcome Test (SNOT-22) total score at Week 24, the need for rescue treatment through Week 24, and the change from baseline in the percent opacification of the bilateral anterior and posterior ethmoids at Week 20, as determined by 3-D volumetric CT analysis.