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

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

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.

Study Overview

• Status: Unknown
• Conditions: Bronchiectasis; Oxidative Stress; Acute Exacerbation of Bronchiectasis
• Intervention / Treatment: Device: medical ultrasonic hydrogen/oxygen nebulizer (MUNHO); Device: Medical molecular mesh oxygen generator

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.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Wei-jie Guan, PhD; Phone Number: +86-13826042052; Email: battery203@163.com
• Study Contact Backup: Name: Nan-shan Zhong, MD; Phone Number: +86-13609003622; Email: nanshan@vip.163.com

Study Locations

• China
  • Chengdu, China
    • Not yet recruiting
    • West China Hospital Affiliateyd to Sichuan Universit
    • Contact: Zong-an Liang
  • Shanghai, China
    • Not yet recruiting
    • Affiliated Zhongshan Hospital of Fudan University
    • Contact: Yuan-lin Song
  • Shanghai, China
    • Not yet recruiting
    • Shanghai Pulmonary Hospital
    • Contact: Jin-fu Xu
  • Guangdong
    • Guangzhou, Guangdong, China
      • Recruiting
      • The Second Affiliated Hospital of Guangzhou Medical University
      • Contact: Fei-peng Chen
    • Guangzhou, Guangdong, China
      • Recruiting
      • First Affiliated Hospital of Guangzhou Medical University
      • Contact: Wei-jie Guan; Email: battery203@163.com
      • Contact: Nan-shan Zhong; Email: nanshan@vip.163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: hydrogen inhalation; 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); 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).; Other Names: hydrogen generating instrument
Sham Comparator: oxygen inhalation; 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; 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.; 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in airway impedance as measured by impulse oscillometry (Z5, R5, R20, X5, Fres and AX at each visit as compared with baseline	Changes in airway impedance as measured by impulse oscillometry (Z5, R5, R20, X5, Fres and AX at each visit as compared with baseline	baseline, month 1, month 3, month 6, month 9 and month 12
Changes in dyshomogeneity (lung clearance index) at month 6 and 12 as compared with baseline	Changes in dyshomogeneity (lung clearance index) at month 6 and 12 as compared with baseline	baseline, month 6 and month 12
Changes in anaerobic threshold (during cardiopulmonary exercise testing) at month 6 and 12 as compared with baseline	Changes in anaerobic threshold (during cardiopulmonary exercise testing) at month 6 and 12 as compared with baseline	baseline, month 6 and month 12
Changes in oxygen pulse (during cardiopulmonary exercise testing) at month 6 and 12 as compared with baseline	Changes in oxygen pulse (during cardiopulmonary exercise testing) at month 6 and 12 as compared with baseline	baseline, month 6 and month 12
Changes in the difference of arterial and alveolar oxygen partial pressure (during cardiopulmonary exercise testing) at month 6 and 12 as compared with baseline	Changes in the difference of arterial and alveolar oxygen partial pressure (during cardiopulmonary exercise testing) at month 6 and 12 as compared with baseline	baseline, month 6 and month 12
Changes in carbon dioxide ventilatory equivalent (during cardiopulmonary exercise testing) at month 6 and 12 as compared with baseline	Changes in carbon dioxide ventilatory equivalent (during cardiopulmonary exercise testing) at month 6 and 12 as compared with baseline	baseline, month 6 and month 12
Changes in 24-hour sputum volume at each visit as compared with baseline	Changes in 24-hour sputum volume at each visit as compared with baseline	baseline, month 1, month 3, month 6, month 9 and month 12
Changes in the levels of sputum inflammatory markers (interleukin-6, interleukin-8 and tumor necrosis factor-α) at month 6 and 12 as compared with baseline	Changes in the levels of sputum inflammatory markers (interleukin-6, interleukin-8 and tumor necrosis factor-α) at month 6 and 12 as compared with baseline	baseline, month 6 and month 12
Changes in sputum matrix metalloproteinases (MMP-8, MMP-9, MMP-9/TIMP-1 ratio) levels at month 6 and 12 as compared with baseline	Changes in sputum matrix metalloproteinases (MMP-8, MMP-9, MMP-9/TIMP-1 ratio) levels at month 6 and 12 as compared with baseline	baseline, month 6 and month 12
The rates of Pseudomonas aeruginosa isolated from sputum at baseline and end-of-treatment at month 6 and 12 as compared with baseline	The rates of Pseudomonas aeruginosa isolated from sputum at baseline and end-of-treatment at month 6 and 12 as compared with baseline	baseline, month 6 and month 12
Sputum microbiota compositions before and after hydrogen therapy	Sputum microbiota compositions before and after hydrogen therapy. This is an exploratory outcome.	up to 12 months (at baseline, month 6, and month 12)
the rate of adverse events	the rate of adverse events	up to 12 months

Collaborators and Investigators

• Sponsor: Guangzhou Institute of Respiratory Disease
• Investigators: Study Chair: Nan-shan Zhong, MD, Guangzhou Institute of Respiratory Disease

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2016
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: May 3, 2016
• First Submitted That Met QC Criteria: May 5, 2016
• First Posted (Estimate): May 6, 2016

Study Record Updates

• Last Update Posted (Actual): August 1, 2019
• Last Update Submitted That Met QC Criteria: July 31, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Inhalation; bronchiectasis; Hydrogen
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Bronchial Diseases; Bronchiectasis; Respiratory Aspiration
• Other Study ID Numbers: GWJ-2015-H2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided