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

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

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).

Study Overview

• Status: Recruiting
• Conditions: COVID-19; Hydrogen-oxygen Gas; AMS-H-03
• Intervention / Treatment: Device: Hydrogen-Oxygen Generator with Nebulizer, AMS-H-03; Other: basic treatment

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 216
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yuanlin Song, PhD; Phone Number: 86-15021757762; Email: ylsong@163.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Zhongshan Hospital Affiliated to Fudan University
      • Contact: Yuanlin Song, PhD; Phone Number: 15021757762; Email: ylsong@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: test group; 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; 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).; Other: basic treatment; supportive treatment determined by the investigator based on the condition of the patients
Active Comparator: Control Group; the control group will use basic treatment only	Other: basic treatment; supportive treatment determined by the investigator based on the condition of the patients

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AE/SAE percentage	AE/SAE percentage	through study completion, an average of 1 year
Rate of device deficiency	Device deficiency refers to the unreasonable risks that may endanger human health and life safety in the normal use of the medical device during the clinical trial, such as label errors, quality problems and malfunctions.	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Shanghai Zhongshan Hospital

Publications and helpful links

General Publications

• Lopez-Leon S, Wegman-Ostrosky T, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, Villapol S. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep. 2021 Aug 9;11(1):16144. doi: 10.1038/s41598-021-95565-8.
• Guan WJ, Wei CH, Chen AL, Sun XC, Guo GY, Zou X, Shi JD, Lai PZ, Zheng ZG, Zhong NS. Hydrogen/oxygen mixed gas inhalation improves disease severity and dyspnea in patients with Coronavirus disease 2019 in a recent multicenter, open-label clinical trial. J Thorac Dis. 2020 Jun;12(6):3448-3452. doi: 10.21037/jtd-2020-057. No abstract available. Erratum In: J Thorac Dis. 2020 Aug;12(8):4591-4592.
• Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, Kang L, Guo L, Liu M, Zhou X, Luo J, Huang Z, Tu S, Zhao Y, Chen L, Xu D, Li Y, Li C, Peng L, Li Y, Xie W, Cui D, Shang L, Fan G, Xu J, Wang G, Wang Y, Zhong J, Wang C, Wang J, Zhang D, Cao B. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021 Jan 16;397(10270):220-232. doi: 10.1016/S0140-6736(20)32656-8. Epub 2021 Jan 8.
• Sanyaolu A, Marinkovic A, Prakash S, Zhao A, Balendra V, Haider N, Jain I, Simic T, Okorie C. Post-acute Sequelae in COVID-19 Survivors: an Overview. SN Compr Clin Med. 2022;4(1):91. doi: 10.1007/s42399-022-01172-7. Epub 2022 Apr 6.
• Huang L, Yao Q, Gu X, Wang Q, Ren L, Wang Y, Hu P, Guo L, Liu M, Xu J, Zhang X, Qu Y, Fan Y, Li X, Li C, Yu T, Xia J, Wei M, Chen L, Li Y, Xiao F, Liu D, Wang J, Wang X, Cao B. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet. 2021 Aug 28;398(10302):747-758. doi: 10.1016/S0140-6736(21)01755-4. Erratum In: Lancet. 2022 May 7;399(10337):1778.
• Blomberg B, Mohn KG, Brokstad KA, Zhou F, Linchausen DW, Hansen BA, Lartey S, Onyango TB, Kuwelker K, Saevik M, Bartsch H, Tondel C, Kittang BR; Bergen COVID-19 Research Group, Cox RJ, Langeland N. Long COVID in a prospective cohort of home-isolated patients. Nat Med. 2021 Sep;27(9):1607-1613. doi: 10.1038/s41591-021-01433-3. Epub 2021 Jun 23.
• Jennings G, Monaghan A, Xue F, Mockler D, Romero-Ortuno R. A Systematic Review of Persistent Symptoms and Residual Abnormal Functioning following Acute COVID-19: Ongoing Symptomatic Phase vs. Post-COVID-19 Syndrome. J Clin Med. 2021 Dec 16;10(24):5913. doi: 10.3390/jcm10245913.
• Zheng ZG, Sun WZ, Hu JY, Jie ZJ, Xu JF, Cao J, Song YL, Wang CH, Wang J, Zhao H, Guo ZL, Zhong NS. Hydrogen/oxygen therapy for the treatment of an acute exacerbation of chronic obstructive pulmonary disease: results of a multicenter, randomized, double-blind, parallel-group controlled trial. Respir Res. 2021 May 13;22(1):149. doi: 10.1186/s12931-021-01740-w.
• Liu ST, Zhan C, Ma YJ, Guo CY, Chen W, Fang XM, Fang L. Effect of qigong exercise and acupressure rehabilitation program on pulmonary function and respiratory symptoms in patients hospitalized with severe COVID-19: a randomized controlled trial. Integr Med Res. 2021;10(Suppl):100796. doi: 10.1016/j.imr.2021.100796. Epub 2021 Oct 29.
• Xiao CX, Lin YJ, Lin RQ, Liu AN, Zhong GQ, Lan CF. Effects of progressive muscle relaxation training on negative emotions and sleep quality in COVID-19 patients: A clinical observational study. Medicine (Baltimore). 2020 Nov 20;99(47):e23185. doi: 10.1097/MD.0000000000023185.

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2022
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: August 16, 2022
• First Submitted That Met QC Criteria: August 16, 2022
• First Posted (Actual): August 17, 2022

Study Record Updates

• Last Update Posted (Actual): August 17, 2022
• Last Update Submitted That Met QC Criteria: August 16, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; Hydrogen-oxygen Gas; AMS-H-03; Hydrogen-Oxygen Generator with Nebulizer
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: AMS-H-03-104

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No