Efficacy and Safety of Hydrogen Inhalation on Bronchiectasis: A Randomized, Multi-center, Double-blind Study

Study Overview
=================
Brief Summary
-----------------
This is a multi-center, randomized, double-blind, parallel-group trial. After a 2-week run-in period, eligible patients will be, based on the randomization codes kept in sealed envelopes, randomly assigned to receive usual care (mucolytics and/or chest physiotherapy) plus oxygen inahaltion (1 hr daily for 12 consecutive months) or hydrogen inhalation (1 hr daily for 12 consecutive months) provided by the sponsor. At 3 months after the end-of-treatment, a follow-up visit will be scheduled for all patients.

Detailed Description
-----------------
This is a multi-center, randomized, double-blind, parallel-group trial. After 2-week run-in period, eligible patients will be, based on the randomization codes kept in sealed envelopes, randomly assigned to two groups.On the basis of usual care [ambroxool (30mg thrice daily), or N-acetylcysteine (0.2g thrice daily)/ serrapeptase (10mg thrice daily), or carbocisteine (500mg thrice daily) and/or chest physiotherapy (10 min, twice daily)], patients were randomized to receive either hydrogen (66.7%, 3L/min, 1 hr twice daily) inhalation or oxygen inhalation (3L/min, 1 hr twice daily) via nasal canula for 12 months. A follow-up visit at month 3 following end-of-treatment was also scheduled. The primary endpoint was the annual frequency of bronchiectasis exacerbations. Hospital visits were scheduled at baseline and months 1, 3, 6, 9, 12 and 15, respectively. At 3 months after the end-of-treatment, a follow-up visit will be scheduled for all patients.

Official Title
-----------------
Efficacy and Safety of Hydrogen Inhalation on Bronchiectasis (HYBRID): A Randomized, Multi-center, Double-blind, Parallel-group Study

Conditions
-----------------
Bronchiectasis, Acute Exacerbation of Bronchiectasis, Oxidative Stress

Intervention / Treatment
-----------------
* Device: medical ultrasonic hydrogen/oxygen nebulizer (MUNHO)
* Device: Medical molecular mesh oxygen generator


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Out-patients of either gender, ex- or never-smokers, aged between 18 and 75 years Clinically stable bronchiectasis, defined as respiratory symptoms and lung function parameters not exceeding normal daily variations and no acute upper respiratory tract infections for 4 consecutive weeks Patients with a history of 2 or more bronchiectasis exacerbations (BEs) within the previous 2 years Exclusion Criteria: Other unstable concomitant systemic illnesses (i.e. coronary heart disease, recent cerebral stroke, severe uncontrolled hypertension, active gastric or duodenal ulcer, uncontrolled diabetes, malignancy, hepatic or renal dysfunction) Concomitant asthma, allergic bronchopulmonary aspergillosis, or active tuberculosis Concomitant chronic obstructive pulmonary disease as the predominant diagnosis Treatment with inhaled, oral or systemic antibiotics within 4 weeks Type 2 respiratory failure needing oxygen therapy or non-invasive mechanical ventilation Females during lactation or pregnancy Poor understanding or failure to properly operate the instrument Participation in other clinical trials within 3 months.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: hydrogen inhalation<br>The medical ultrasonic nebulizers with hydrogen/oxygen generating function (MUNHO) will be provided exclusively by the sponsor, Asclepius Meditec Inc (Shanghai, China). The MUNHO consists of a electrolytic tank which, by using direct current converted from alternating current (220 V), generates the hydrogen and oxygen gas from pure water (2:1 in volume). The MUNHO is also capable of nebulizing the water via ultrasounds with the hydrogen-oxygen mixture gas which is finally delivered to the patient's airways via the facial mask through a plastic tube. Typically, the volume of hydrogen-oxygen mixed gas is 3 liters per minute (3 L/min). Usual care referred to mucolytics (see below for details) alone or plus chest physiotherapy. | Device: medical ultrasonic hydrogen/oxygen nebulizer (MUNHO)<br>* The medical ultrasonic nebulizers with hydrogen/oxygen generating function (MUNHO) will be provided exclusively by the sponsor, Asclepius Meditec Inc (Shanghai, China). The MUNHO consists of a electrolytic tank which, by using direct current converted from alternating current (220 V), generates the hydrogen and oxygen gas from pure water (2:1 in volume). The MUNHO is also capable of nebulizing the water via ultrasounds with the hydrogen-oxygen mixed gas which is finally delivered to the patient's airways via the facial mask through a plastic tube. Typically, the volume of hydrogen-oxygen mixed gas is 3 liters per minute (3 L/min).<br>* Other names: hydrogen generating instrument;|
| Sham Comparator: oxygen inhalation<br>Oxygen will be generated by an instrument provided by the sponsor, that would be capable of generating oxygen equivalent to that generated by the MUNHO (3L/min mixed gas containing 33.3% oxygen). Usual care referred to mucolytics [[ambroxool (30mg thrice daily), or N-acetylcysteine (0.2g thrice daily)/ serrapeptase (10mg thrice daily), or carbocisteine (500mg thrice daily)] alone or in combination with chest physiotherapy. | Device: Medical molecular mesh oxygen generator<br>* medical molecular mesh oxygen generator, type: OLO-1, oxygen flow: 3L/min; Shanghai Ouliang Medical Instrument Inc., Shanghai, China; Registration No.: Shanghai Medical Instrument approval No. 20152540046. This device has an identical appearance as compared with the MUHNO so that the patients could not readily discriminate with the MUHNO, and is also capable of displaying the actual cumulative duration of oxygen inhalation.<br>* Other names: Oxygen generating instrument;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of bronchiectasis exacerbations (BEs) within 12 months | Frequency of bronchiectasis exacerbations (BEs) within 12 months | up to 12 months (1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in sputum oxidant (hydrogen peroxide, reactive oxygen species) levels at month 6 and 12 as compared with baseline | Changes in sputum oxidant (hydrogen peroxide, reactive oxygen species) levels at month 6 and 12 as compared with baseline | baseline, month 6 and month 12 | 
| Time to the first bronchiectasis exacerbations (BEs) within 12 months | Time to the first bronchiectasis exacerbations (BEs) within 12 months | up to 12 months | 
| Changes in sputum antioxidants levels (catalase, superoxide dismutase and total antioxidant capacity) at month 6 and 12 as compared with baseline | Changes in sputum antioxidants levels (catalase, superoxide dismutase and total antioxidant capacity) at month 6 and 12 as compared with baseline | baseline, month 6 and month 12 | 
| Changes in serum oxidant (hydrogen peroxide, reactive oxygen species) levels at month 6 and 12 as compared with baseline | Changes in serum oxidant (hydrogen peroxide, reactive oxygen species) levels at month 6 and 12 as compared with baseline | baseline, month 6 and month 12 | 
| Changes in serum antioxidants levels (catalase, superoxide dismutase and total antioxidant capacity) at month 6 and 12 as compared with baseline | Changes in serum antioxidants levels (catalase, superoxide dismutase and total antioxidant capacity) at month 6 and 12 as compared with baseline | baseline, month 6 and month 12 | 
| Changes in spirometry, including FEV1, FEV1/FVC ratio and MMEF at each visit following randomization as compared with baseline | Changes in spirometry, including FEV1, FEV1/FVC ratio and MMEF at each visit following randomization as compared with baseline | baseline, month 1, month 3, month 6, month 9 and month 12 | 
| Changes in CRP levels at month 6 and 12 as compared with baseline | Changes in CRP levels at month 6 and 12 as compared with baseline | baseline, month 6 and month 12 | 
| Changes in quality of life assessed by using Quality-of-Life Questionnaire--Bronchiectasis (QoL-B) at month 6 and 12 as compared with baseline | Changes in quality of life assessed by using Quality-of-Life Questionnaire--Bronchiectasis (QoL-B) at month 6 and 12 as compared with baseline | baseline, month 6 and month 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hydrogen, Inhalation, bronchiectasis