Evaluation of Nacystelyn Dry-Powder Inhaler in the Treatment of Obstructive Sleep Apnea: A Double-Blind, Placebo-Controlled, Parallel-Group Study

The primary objective of this study is to evaluate the potential therapeutic benefits of **Nacystelyn** (NAL) Dry-Powder Inhaler (DPI) in the treatment of **Obstructive Sleep Apnea** (OSA). This is clinically relevant as OSA is a prevalent condition associated with significant morbidity, and effective treatments are essential for improving patient outcomes and quality of life.

Secondary objectives include:

• Assessing the efficacy of NAL DPI as an antioxidant in mitigating oxidative stress induced by OSA.
• Evaluating the overall safety profile of NAL DPI.

The clinical trial involves participants diagnosed with **obstructive sleep apnea** (OSA). The study population includes both male and female adults, with an age range of 18 to 55 years. Participants are required to have an apnea-hypopnoea index (AHI) between 15 and 30 events per hour and an oxygen desaturation index of at least 10. The trial includes individuals who are either naïve to CPAP therapy or have not been treated with CPAP for at least two months. Participants must have a body mass index (BMI) between 18 and 35 kg/m². Women of childbearing potential are required to adhere to specified contraceptive measures, while those of non-childbearing potential must meet criteria such as being postmenopausal or surgically sterile. The trial population was selected based on these criteria, and participants must voluntarily agree to participate by signing an informed consent form. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the effects of **Nacystelyn** (NAL) in patients with **Obstructive Sleep Apnea** (OSA). This study is a randomized, double-blind, placebo-controlled, parallel-group trial. The primary objective is to assess the efficacy of NAL delivered via a dry-powder inhaler in reducing the Apnea-Hypopnea Index (AHI) over a treatment period of six weeks. The trial is expected to commence on April 1, 2024, and conclude by November 30, 2024.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as an AHI between 15 and 30 events per hour, a BMI between 18 and 35 kg/m², and no recent treatment with CPAP. Following successful screening, participants will be randomized to receive either NAL or a placebo. The study will include regular follow-up visits to monitor safety, adherence, and efficacy, with assessments of primary and secondary endpoints, including changes in respiratory indices and patient-reported outcomes.

The trial will involve a total of six weeks of active treatment, with participants required to attend multiple visits throughout this period. The end-of-study visit will occur at the conclusion of the treatment phase, where final assessments will be conducted. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of **Nacystelyn** (NAL), a chemical-origin medication, in the form of a **capsule**. The active substance, **L-Lysine-N-Acetyl-L-Cystein** (Nacystelyn), is provided by LABORATOIRES SMB S.A. The pharmaceutical form is a capsule, and the medication is administered via **inhalation** using a monodose dry powder inhaler, specifically the AXAHALER, which is a Class 1 medical device. The maximum daily dose for this formulation is 40 mg, with a treatment period not exceeding six months. The inhalation route ensures direct delivery to the respiratory system, which is pertinent for the study's focus on obstructive sleep apnea.

Another formulation of **Nacystelyn** is used in the trial as an **inhalation powder, hard capsule**. This formulation also originates from LABORATOIRES SMB S.A. and is administered via inhalation using the same AXAHALER device. The maximum daily dose for this formulation is 80 mg, with a similar treatment period of up to six months. The use of the AXAHALER device ensures precise delivery of the medication when the participant inhales, facilitating effective treatment of obstructive sleep apnea.

The study also includes a **placebo** group, which receives a placebo of NAL. The placebo is designed to mimic the active treatment without containing the active substance, ensuring the study's double-blind design. The placebo is administered in a manner consistent with the active treatment to maintain the integrity of the study's blinding process. The placebo does not have a specified pharmaceutical form or active substance, as it serves as a control to evaluate the efficacy of the active treatment.

The efficacy of the investigational product, **Nacystelyn** (NAL), in the treatment of obstructive sleep apnea (OSA) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the mean change in the Apnea-Hypopnea Index (PSG-AHI3%) from baseline to 6 weeks of treatment. This will be measured using polysomnography, a standard diagnostic tool for sleep disorders.

Secondary endpoints include a variety of parameters to provide a comprehensive evaluation of treatment effects. These parameters include absolute changes from baseline to week 6 in the mandibular movement respiratory disturbance index (MM-RDI), mandibular movement respiratory effort (MM-RE), and apnea-hypopnea index (AHI) measured by Sunrise®. Additional secondary endpoints involve changes in the number of apnea and hypopnea episodes, the longest apneic episode duration, and various oxygen saturation metrics such as the oxygen desaturation index (ODI), time under 90% oxygen saturation (T90%), mean arterial oxygen saturation (MSaO2), and lowest arterial oxygen saturation (LSaO2).

Further assessments will include changes in pulse wave amplitude drops (PWADs) index, snore metrics, Epworth sleepiness score (ESS), and participant-reported outcomes from the nasal obstruction symptom evaluation (NOSE) questionnaire, Pichot’s fatigue scale, and Patient Health Questionnaire (PHQ-9). Biomarkers of oxidative stress and inflammation will also be evaluated. Safety and tolerability will be monitored through adverse events, vital signs, physical examinations, and concomitant medication use. The efficacy assessments will be conducted at baseline and at the end of the 6-week treatment period.