Hydrogen-Oxygen Generator With Nebulizer for Rehabilitation Treatment of COVID-19

Study Overview
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Brief Summary
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This is a prospective, multicenter, randomized, controlled, superiority clinical trial, with the test group expected to be superior to the control group in the primary evaluation endpoints (changes in Borg score and PSQI index at 3 months after the start of the treatment). The test group will use the investigational device Hydrogen-Oxygen Generator with Nebulizer (manufactured by Shanghai Asclepius Meditec Co., Ltd.) + basic treatment (supportive treatment determined by the investigator based on the condition of the patients), and the control group will use basic treatment only, to evaluate of effectiveness and safety of the investigational device Hydrogen-Oxygen Generator with Nebulizer for rehabilitation treatment of dysfunctions in discharged patients who are previously hospitalized due to 2019 novel coronavirus pneumonia (COVID-19).

Detailed Description
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A total of 216 eligible subjects will be randomly assigned to the test group and the control group in a 1:1 ratio to receive corresponding treatment (treatment in both groups will last for 12 months), and the subjects will then be followed up for 12 months from the start of treatment after enrollment. All subjects enrolled in this study will receive seven visits, including the screening visit (within 14 days before the enrollment), randomization and treatment visit (Day 0), visits at 1 month after the start of the treatment (± 7 days), 2 months after the start of the treatment (± 7 days), 3 months (± 14 days) after the start of the treatment, 6 months (± 14 days) after the start of the treatment, and 12 months (± 30 days) after the start of the treatment. The following indicators of the two groups will be collected and analyzed in this study: the primary effectiveness evaluation indicator: changes in Borg score and PSQI index at 3 months after the start of the treatment; secondary effectiveness evaluation indicators: 1) Pulmonary function assessment indicators (forced expiratory volume in one second [FEV1], ratio of forced expiratory volume in one second to forced vital capacity [FEV1/FVC], 25/50/75% maximal mid expiratory flow [MMEF 25/50/75], and fractional exhaled nitric oxide [FeNO]); 2) Lung imaging changes; 3) Neurological and psychological function assessment indicators (Mini-Mental State Examination Scale [MMSE] score, Generalized Anxiety Disorder Scale [GAD-7] score, Depression Screening Scale [PHQ-9] score, Post-Traumatic Stress Disorder Checklist [PCL-C]); 4) Inflammatory indicators (neutrophil-to-lymphocyte ratio [NLR], C-reactive protein [CRP], interleukin-6 [IL-6]); 5) Evaluation of device usability, and the safety evaluation indicators: incidence of AEs and SAEs, and incidence of device deficiencies. When all enrolled subjects have completed the follow up at 3 months after the start of the treatment, an analysis will be performed for application to the National Medical Products Administration (NMPA) for registration of the investigational medical device, while the 6- and 12-month follow up will be continued spontaneously.

Official Title
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A Randomized, Controlled Clinical Trial to Evaluate the Effectiveness and Safety of Hydrogen-Oxygen Generator With Nebulizer for Rehabilitation Treatment of Dysfunctions in Discharged Patients Who Are Previously Hospitalized Due to COVID-19

Conditions
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COVID-19, AMS-H-03, Hydrogen-oxygen Gas

Intervention / Treatment
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* Device: Hydrogen-Oxygen Generator with Nebulizer, AMS-H-03
* Other: basic treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects aged between 18 and 75 years old (inclusive); Subjects previously hospitalized due to COVID-19, who are recovered and discharged with negative results for COVID-19 and released from quarantine; Known symptoms of respiratory dysfunctions (such as dyspnea), and / or neurological/psychological dysfunction (such as sleep disorders, anxiety, and depression) and / or somatic dysfunction (such as fatigue); Borg dyspnea or fatigue score before study treatment ≥ 1 (please refer to Appendix 2: Borg Scale for specific information), and PSQI score ≥ 2 (please refer to Appendix 3: PSQI Scale for specific information); Subjects who are willing to participate and provided written informed consent form. Exclusion Criteria: Subjects with known malignant tumor; Subjects with known moderate or severe pulmonary infection; Subjects with mucosa injury in upper respiratory tract, for whom no inhalation treatment can be provided; Subjects who are intolerable to inhalation treatment; Subjects with moderate or severe disabilities; Subjects with mental disorders or cognitive impairment who are unable to provide consent; Subjects with neurological disease accompanied with sleep disorders for which medical intervention is provided before the diagnosis of COVID-19. Subjects with any immunodeficiency (for example, subjects requiring chronic treatment with any corticosteroid or other immunosuppressants) judged by the investigator; Allergy to any component of the investigational product that have contact with human body; Complicate severe cardiac, hepatic or renal insufficiency; Expected life expectancy < 1 year; Subjects who are participating in any other clinical study of any investigational drug or medical device; Pregnant or lactating women, or women who plan to become pregnant within the following one year; Any other condition judged as inappropriate to participate in this study by the investigator.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The test group will use the investigational device Hydrogen-Oxygen Generator with Nebulizer (manufactured by Shanghai Asclepius Meditec Co., Ltd.) + basic treatment (supportive treatment determined by the investigator based on the condition of the patients), and the control group will use basic treatment only
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: test group<br>The test group will use the investigational device Hydrogen-Oxygen Generator with Nebulizer (manufactured by Shanghai Asclepius Meditec Co., Ltd.) + basic treatment (supportive treatment determined by the investigator based on the condition of the patients) | Device: Hydrogen-Oxygen Generator with Nebulizer, AMS-H-03<br>* Treatments in the test group will lasts for 12 months, and symptomatic treatment will be provided based on the actual symptoms of the subjects. Subjects in the test group will be required to receive inhalation for at least 4 days every 7 days with at least 3780L inhaled every 7 days (It is recommended to inhale at least 540L per day; If the flow rate is 3L/min, it is recommended that the cumulative inhalation time should be at least 3 hours per day. If the flow rate is 1.5L/min, it is recommended that the cumulative inhalation time should be at least 6 hours per day).<br>Other: basic treatment<br>* supportive treatment determined by the investigator based on the condition of the patients<br>|
| Active Comparator: Control Group<br>the control group will use basic treatment only | Other: basic treatment<br>* supportive treatment determined by the investigator based on the condition of the patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Borg score index from baseline at 3 months after the start of the study treatment. | after the start of the treatment compared to Borg score assessed after the 6-minute walk test before treatment in the test or the control group. | Changes in Borg score assessed after the 6-minute walk test at 3 months (±7 days) | 
| Changes in PSQI index from baseline at 3 months after the start of the study treatment. | Changes in PSQI index at 3 months (±7 days) after the start of the treatment of the subjects in the test group or the control group compared with that before treatment. | Changes in PSQI index at 3 months (±7 days) after the start of the treatment of the subjects in the test group or the control group compared with that before treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary function evaluation: FEV1 | Pulmonary function evaluation: FEV1 | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Change in imaging evaluation | It is defined as the change in lung imaging results evaluated by CT examination | 3 months (±14 days), 6 months (±14 days, as needed), and 12 months (±30 days) | 
| Neurological and psychological function indicators including MMSE score | Neurological and psychological function indicators including MMSE score | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Inflammatory indicators, including NLR | Inflammatory indicators, including NLR | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Usability evaluation of the medical device | It is defined as the results of the evaluation on usability of the investigational medical device conducted according to the following table | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Pulmonary function evaluation: FEV1/FVC | Pulmonary function evaluation: FEV1/FVC | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Pulmonary function evaluation: MMEF 25 | Pulmonary function evaluation: MMEF 25 | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Pulmonary function evaluation: MMEF50 | Pulmonary function evaluation: MMEF 50 | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Pulmonary function evaluation: MMEF 75 | Pulmonary function evaluation: MMEF 75 | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Pulmonary function evaluation: FeNO | Pulmonary function evaluation: FeNO | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Neurological and psychological function indicators including GAD-7 score | Neurological and psychological function indicators including GAD-7 score | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Neurological and psychological function indicators including PHQ-9 score | Neurological and psychological function indicators including PHQ-9 score | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Neurological and psychological function indicators including PCL-C score | Neurological and psychological function indicators including PCL-C score | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Inflammatory indicators, including CRP | Inflammatory indicators, including CRP | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 
| Inflammatory indicators, including IL-6 | Inflammatory indicators, including IL-6 | 1 month (±7 days), 2 months (±7 days), 3 months (±14 days), 6 months (±14 days) and 12 months (±30 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Hydrogen-Oxygen Generator with Nebulizer, AMS-H-03, Hydrogen-oxygen Gas