Evaluation of 7% Hypertonic Saline Inhalation and ELTGOL Physiotherapy on Mucus Clearance in Bronchiectasis Patients: A Randomized Controlled Trial

The primary objective of this study is to evaluate the effect of the combination of once-daily **7% hypertonic saline** and twice-daily ELTGOL technique on **mucus clearance** in patients with **bronchiectasis**. This is compared to both once-daily isotonic saline with twice-daily ELTGOL technique and to the twice-daily ELTGOL technique alone. The clinical relevance of this objective lies in its potential to improve mucus clearance, which is a critical aspect of managing bronchiectasis, thereby potentially enhancing patient outcomes and quality of life.

Secondary objectives include:

• Evaluating the effects of the three treatment regimes on the impact of cough, exacerbations, mucus properties, quality of life, sputum cultures, and pulmonary function in these patients.
• Assessing possible side effects.
• Assessing adherence to the different regimes.
• Determining whether the effects are sustained one month after the treatment is ended.

The clinical trial focuses on evaluating the effect of a combination therapy involving once-daily 7% hypertonic saline and twice-daily ELTGOL technique on **mucus clearance** in patients with bronchiectasis. The study population includes both men and women aged 18 years and older, with bronchiectasis confirmed by high-resolution computed tomography. Participants are required to have no exacerbations in the previous month, chronic purulent sputum with a daily expectoration of at least 10ml, and at least one exacerbation in the previous year. Additionally, participants must have a forced expiratory volume in one second (FEV1) of 30% or more after bronchodilation and must sign the informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the effect of a combination therapy involving once-daily inhalation of 7% hypertonic saline and twice-daily ELTGOL physiotherapy on mucus clearance in patients with **bronchiectasis**. This study is a randomized, controlled trial with a double-blind design to ensure unbiased results. The trial is expected to last for a total duration of 12 months, with participant recruitment anticipated to begin on March 4, 2024, and the study concluding by March 2, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), confirmed bronchiectasis via high-resolution computed tomography, and other health parameters. Following the screening, participants will be randomized into different treatment groups. The primary endpoint is the change in sputum weight from baseline to the seventh visit (V7). Secondary endpoints include changes in 24-hour sputum volume, cough assessment, number of exacerbations, and quality of life over the 12-month period.

Study visits will occur at regular intervals, with key assessments at visits V2, V3, V5, and V7, including evaluations of treatment adherence, adverse events, and pulmonary function tests. The end-of-study visit (V8) will assess changes in sputum characteristics, quality of life, and lung function from V7. Participants are expected to be involved in the study for the entire 12-month period unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent.

The trial involves the administration of two medicinal products: a test product, **sodium chloride** (7% hypertonic saline), and a comparator, electrolytes (sodium, potassium), both delivered via inhalation. The maximum daily dose for the test product is 5 ml, while the comparator is limited to 1 ml. The study aims to provide valuable insights into the efficacy of hypertonic saline in enhancing mucus clearance when used in conjunction with physiotherapy in patients with bronchiectasis.

The clinical trial involves the administration of **sodium hydrogen carbonate Ph. Eur.**, commonly known as sodium bicarbonate, as an experimental treatment. This substance is delivered in the form of a **7% hypertonic saline solution**. The pharmaceutical form is identified as PHF00169MIG, and the administration route is via **inhalation**. The maximum daily dose is 5 ml, with a total maximum dose of 5 ml per day. The treatment period is set for a maximum of 12 weeks. The primary objective is to assess the efficacy of this treatment in enhancing mucus clearance in patients with bronchiectasis when used in conjunction with the ELTGOL physiotherapy technique.

The comparator treatment in this study is a solution containing **electrolytes**, specifically sodium and potassium. This solution is also administered via inhalation, with a pharmaceutical form designated as PHF00230MIG. The maximum daily dose for this treatment is 1 ml, with a total maximum dose of 1 ml per day, over a treatment period of up to 12 weeks. This comparator aims to evaluate the relative effectiveness of the hypertonic saline solution against a standard electrolyte solution in the context of bronchiectasis treatment.

Both treatments are non-paediatric formulations and are not classified as orphan drugs. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial seeks to provide insights into the benefits of hypertonic saline inhalation prior to ELTGOL physiotherapy compared to isotonic saline and the ELTGOL technique alone.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in sputum weight in grams from baseline to visit 7 (V7) during the intervention. Secondary endpoints include changes from baseline in 24-hour sputum volume and weight over the 12-month treatment period, changes in cough as assessed by the Leicester Cough Questionnaire from visit 2 (V2), and the number of exacerbations and time to the first exacerbation over the same period. Additional secondary endpoints involve changes in sputum purulence, assessed by a sputum color chart, mucus properties, and microbiology from V2 to V7, as well as changes in quality of life measured by the Bronchiectasis Health Questionnaire and the Saint George Respiratory Questionnaire from V2.

Further assessments include changes in post-bronchodilator **FEV1** in milliliters from V2 over the 12-month period, treatment adherence evaluated through vial counting, the Morisky-Green test, and a diary card. Adverse events will be monitored by symptoms reported, vital sign measurements (including blood pressure and arterial oxygen saturation), physical examinations, and the Borg scale at the end of interventions at V2, V3, V5, V7, and pulmonary function tests at V2. Additionally, changes from V7 to V8 in 24-hour sputum volume, color, weight, quality of life, and **FEV1** will be evaluated. These efficacy parameters will be collected and analyzed at specified time points throughout the trial to determine the impact of the treatment regimen on patients with bronchiectasis.