Hypertonic Saline Inhalation for Nontuberculous Mycobacterial Lung Disease

Official title

A Randomized Controlled Trial of Early Versus Delayed Hypertonic Saline Inhalation in Treatment-Naïve Nontuberculous Mycobacterial Lung Disease

Overview

This multicenter randomized controlled trial evaluates the clinical and microbiological effects of inhaled 3% hypertonic saline in treatment-naïve patients with nontuberculous mycobacterial lung disease (NTM-LD). Participants are randomized in a 1:1 ratio to either early initiation of 3% hypertonic saline for 6 months or delayed initiation consisting of normal saline inhalation during the first 3 months followed by 3% hypertonic saline during the subsequent 3 months. The primary objective is to compare respiratory symptom improvement between hypertonic saline and normal saline at Month 3. Secondary objectives include evaluating sputum microbiological outcomes, radiographic changes, inflammatory markers, small airway function, treatment initiation, safety, and within-participant changes before and after switching from normal saline to hypertonic saline in the delayed-initiation arm. The first participant was enrolled on October 3, 2025.

Detailed description

Nontuberculous mycobacterial lung disease (NTM-LD) is a chronic pulmonary infection that frequently progresses despite conservative management. Because prolonged multidrug antibiotic therapy is associated with substantial treatment burden, potential toxicity, and variable effectiveness, additional non-antibiotic treatment strategies are needed, particularly for patients who defer, cannot tolerate, or are not yet indicated for antibiotic treatment.

Hypertonic saline inhalation facilitates airway clearance and sputum removal and has been increasingly used as an adjunctive treatment in specialized NTM centers. However, prospective randomized data remain limited, particularly in Asian populations.

This multicenter randomized controlled trial investigates whether early initiation of inhaled 3% hypertonic saline improves respiratory symptoms and microbiological outcomes compared with delayed initiation.

To ensure treatment safety, all participants undergo a supervised inhalation tolerance assessment before randomization. During this assessment, inhaled salbutamol (Ventolin) premedication is administered, followed by inhalation of 3% hypertonic saline. Participants demonstrating clinically significant intolerance, severe bronchospasm, or other safety concerns are excluded from study treatment.

Following successful completion of the tolerance assessment, participants are randomized to one of two groups.

The early-initiation group receives inhaled 3% hypertonic saline for 6 months. The delayed-initiation group receives inhaled normal saline during Months 0-3, followed by inhaled 3% hypertonic saline during Months 4-6.

The primary randomized comparison is performed at Month 3 between participants receiving hypertonic saline and those receiving normal saline. Additional analyses evaluate within-participant changes in the delayed-initiation arm before and after switching from normal saline to hypertonic saline.

Throughout the study, participants continue routine clinical care. Initiation of anti-NTM antibiotic treatment remains at the discretion of the treating physician.

Interventions

• Drug Nebulized 3% Hypertonic Saline
  Nebulized 3% hypertonic saline, 5 mL once daily via mesh nebulizer. Administered during Months 0-6 in the early-initiation arm and during Months 4-6 in the delayed-initiation arm after completion of the Month 3 assessment.
• Drug Nebulized Normal Saline
  Nebulized 0.9% normal saline, 5 mL once daily via mesh nebulizer during Months 0-3 in the delayed-initiation arm.

Primary outcome measures

• Change in Total Respiratory Severity Score (RSS) From Baseline to Month 3 [Time frame: Baseline and Month 3]

Secondary outcome measures (11)

• Change in Acid-Fast Bacilli (AFB) Sputum Smear Grade Over Time [Time frame: Baseline, Month 3, and Month 6]
• Change in Mycobacterial Sputum Culture Status Over Time [Time frame: Baseline, Month 3, and Month 6]
• Change in Radiographic Severity Score From Baseline to Month 6 [Time frame: Baseline and Month 6]
• Change in Erythrocyte Sedimentation Rate (ESR) From Baseline to Month 6 [Time frame: Baseline and Month 6]
• Change in R5-R20 Measured by Impulse Oscillometry From Baseline to Month 6 [Time frame: Baseline and Month 6]
• Change in Post-Bronchodilator FEV1 (% Predicted) From Baseline to Month 6 [Time frame: Baseline and Month 6]
• Anti-NTM Treatment Initiation [Time frame: Up to Month 6]
• Adverse Events [Time frame: Up to Month 6]
• Within-Participant Change in Respiratory Severity Score During Normal Saline and Hypertonic Saline Treatment Periods in the Delayed-Initiation Arm [Time frame: Baseline to Month 6]
• Change in Respiratory Severity Score From Month 3 to Month 6 in the Early-Initiation Arm [Time frame: Month 3 and Month 6]
• Change in Total RSS at Month 6 [Time frame: Baseline and Month 6]

Eligibility criteria

Inclusion criteria

• Adults aged 18 years or older.
• Diagnosis of nontuberculous mycobacterial lung disease (NTM-LD) according to ATS/ERS/ESCMID/IDSA diagnostic criteria, including compatible clinical symptoms, radiographic findings, and microbiological evidence.
• Not receiving anti-NTM antibiotic treatment at the time of screening.
• Able and willing to provide written informed consent.
• Able to perform nebulized inhalation therapy using a mesh nebulizer at home.

Exclusion criteria

• Active tuberculosis.
• Human immunodeficiency virus (HIV) infection.
• Receiving active treatment for malignancy.
• Uncontrolled asthma.
• Frequent or clinically significant hemoptysis.
• History of intolerance, bronchospasm, or hypersensitivity during inhalation testing with hypertonic saline.
• Inability to prepare a mesh nebulizer or perform inhalation therapy at home.
• Any condition that, in the opinion of the investigator, would make participation unsafe or interfere with study participation.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Taiwan · 1 center

• Taipei Veterans General Hospital — Taipei

Publications

• Huiberts A, Zweijpfenning SMH, Pennings LJ, Boeree MJ, van Ingen J, Magis-Escurra C, Hoefsloot W. Outcomes of hypertonic saline inhalation as a treatment modality in nontuberculous mycobacterial pulmonary disease. Eur Respir J. 2019 Jul 11;54(1):1802143. doi: 10.1183/13993003.02143-2018. Print 2019 Jul. No abstract available. PMID 31000680
• Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr, Andrejak C, Bottger EC, Brozek J, Griffith DE, Guglielmetti L, Huitt GA, Knight SL, Leitman P, Marras TK, Olivier KN, Santin M, Stout JE, Tortoli E, van Ingen J, Wagner D, Winthrop KL. Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline. Clin Infect Dis. 2020 Aug 14;71(4): PMID 32628747

Identifiers

NCT: NCT07647575 · HiNTM-01 · 114-2314-B-075 -079 · 2025-02-019A

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗