Hydrogen-Oxygen Generator With Nebulizer for Adjuvant Treatment of Novel Coronavirus Disease 2019 (COVID-19)

A Multi-center, Randomized, Parallel Controlled, Double-Blinded Clinical Trial to Evaluate the Effectiveness and Safety of Hydrogen-Oxygen Generator With Nebulizer for Adjuvant Treatment of Novel Coronavirus Disease 2019 (COVID-19)

This is a multi-center, randomized, parallel controlled, double-blinded clinical trial to evaluate the effectiveness and safety of Hydrogen-Oxygen Generator with Nebulizer for adjuvant treatment of COVID-19 patients. The test group is expected to be superior to the control group in the primary endpoint (percentage of subjects achieving clinical recovery at Day 7 of study treatment). Subjects in the test group will receive treatment by using Hydrogen-Oxygen Generator with Nebulizer (manufactured by Shanghai Asclepius Meditec Co., Ltd., flow rate: 3L/min) combined with conventional basic supportive treatment (symptomatic support treatment determined by the investigator based on the condition of the subjects); and subjects in the control group will receive treatment by using Medical Molecular Sieve Oxygen Generator (manufactured by Shanghai Ouliang Medical Devices Co., Ltd., flow rate: 3L/min, provided by the sponsor) combined with conventional basic supportive treatment (same with that in the test group).

Study Overview

• Status: Not yet recruiting
• Conditions: Covid19; Hydrogen-oxygen Gas; AMS-H-03
• Intervention / Treatment: Device: Hydrogen-Oxygen Generator with Nebulizer, AMS-H-03; Device: OLO-1 Medical Molecular Sieve Oxygen Generator

Detailed Description

Data of the following effectiveness and safety endpoints of subjects in the two groups will be collected and analyzed in this study, including of the primary effectiveness endpoint: percentage of subjects achieving clinical recovery at Day 7 of study treatment; and the secondary effectiveness endpoints: percentage of subjects achieving clinical recovery on Day 2, 3, 5, 10 of study treatment and that before discharge; percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more on Day 2, 3, 5, 7, 10 of study treatment and before discharge; reduction of WHO Clinical Progression Scale score on Day 2, 3, 5, 7, 10 of study treatment and before discharge; changes in COVID-19 symptom scores on Day 2, 3, 5, 7, 10 of study treatment and before discharge; total length of hospital stay; time from randomization to conversion to general COVID-19; time from randomization to conversion to mild COVID-19 disease; percentage of patients with no fever, shortness of breath and chest pain on Day 2, 3, 5, 7, 10 of study treatment and before discharge; Oxygen saturation based on finger blood samples in resting non-oxygen inhalation state; and safety evaluation variables including incidences of AEs, SAEs and device deficiencies.

• Study Type: Interventional
• Enrollment (Anticipated): 218
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Guan Wei-jie, PhD; Phone Number: +86-13826042052; Email: battery203@163.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • First Affiliated Hospital of Guangzhou Medical University

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:

1. Male or female subjects aged between 18 and 75 years old (inclusive).
2. Diagnosed with mild, moderate or severe type of COVID-19 according to the criteria of Scheme for Diagnosis and Treatment of 2019 Novel Coronavirus Pneumonia (Trial Version 10).
3. Positive result for COVID-19 nucleic acid test or rapid antigen detection at screening visit;
4. Presenting with at least one respiratory symptom (e.g. dyspnoea, shortness of breath) at hospital admission.
5. Be willing to participate in this trial and provide written informed consent form.

Exclusion Criteria:

1. Subjects with critical or asymptomatic type of COVID-19;
2. Subjects with any known malignant tumor or life expectancy less than half a year.
3. Subjects who are intolerable to inhalation treatment.
4. Subjects with mental disorders or cognitive impairment who are unable to provide consent.
5. Subjects with any immunodeficiency requiring chronic treatment with any corticosteroid or other immunosuppressants.
6. Complicate with any serious cardiac, hepatic or renal disease (as indicated by aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≥ 2 × upper limit of normal [ULN], or creatinine ≥ 176.8mmol/L, or New York Heart Association (NYHA) Classification for heart failure of Class IV) or any serious primary systematic disease.
7. Subjects who are going to use any non-expectorant antioxidant drug, including large doses of vitamin C and vitamin E during the study period.
8. Subjects who are participating in any other clinical study on any investigational drug or medical device.
9. Pregnant or lactating women.
10. Subjects with 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: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: experimental Group; Subjects in the experimental group will receive treatment by using Hydrogen-Oxygen Generator with Nebulizer (manufactured by Shanghai Asclepius Meditec Co., Ltd., flow rate: 3L/min) combined with conventional basic supportive treatment (symptomatic support treatment determined by the investigator based on the condition of the subjects);	Device: Hydrogen-Oxygen Generator with Nebulizer, AMS-H-03; Subjects in the experimental group will receive treatment by using Hydrogen-Oxygen Generator with Nebulizer (manufactured by Shanghai Asclepius Meditec Co., Ltd., flow rate: 3L/min) combined with conventional basic supportive treatment (symptomatic support treatment determined by the investigator based on the condition of the subjects);
Active Comparator: Control Group; subjects in the control group will receive treatment by using Medical Molecular Sieve Oxygen Generator (manufactured by Shanghai Ouliang Medical Devices Co., Ltd., flow rate: 3L/min, provided by the sponsor) combined with conventional basic supportive treatment (same with that in the test group).	Device: OLO-1 Medical Molecular Sieve Oxygen Generator; subjects in the control group will receive treatment by using Medical Molecular Sieve Oxygen Generator (manufactured by Shanghai Ouliang Medical Devices Co., Ltd., flow rate: 3L/min, provided by the sponsor) combined with conventional basic supportive treatment (same with that in the test group).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the percentage of subjects with clinical recovery on Day 7 of study treatment.	continuous clinical recovery is defined as score (see Appendix 2) of COVID-19 related symptoms ≤ 1 continued for 2 consecutive days or discharge criteria is met. Time of continuous clinical recovery is defined as time (days) between the first initiation of the study treatment devices and the time when the score of relevant COVID-19 related symptoms ≤ 1 continues for 2 consecutive days or discharge criteria is met (whichever comes first).	Day 7of study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of subjects achieving clinical recovery	continuous clinical recovery is defined as score (see Appendix 2) of COVID-19 related symptoms ≤ 1 continued for 2 consecutive days or discharge criteria is met. Time of continuous clinical recovery is defined as time (days) between the first initiation of the study treatment devices and the time when the score of relevant COVID-19 related symptoms ≤ 1 continues for 2 consecutive days or discharge criteria is met (whichever comes first).	Day 2of study treatment
Percentage of subjects achieving clinical recovery	continuous clinical recovery is defined as score (see Appendix 2) of COVID-19 related symptoms ≤ 1 continued for 2 consecutive days or discharge criteria is met. Time of continuous clinical recovery is defined as time (days) between the first initiation of the study treatment devices and the time when the score of relevant COVID-19 related symptoms ≤ 1 continues for 2 consecutive days or discharge criteria is met (whichever comes first).	Day 3 of study treatment
Percentage of subjects achieving clinical recovery	continuous clinical recovery is defined as score (see Appendix 2) of COVID-19 related symptoms ≤ 1 continued for 2 consecutive days or discharge criteria is met. Time of continuous clinical recovery is defined as time (days) between the first initiation of the study treatment devices and the time when the score of relevant COVID-19 related symptoms ≤ 1 continues for 2 consecutive days or discharge criteria is met (whichever comes first).	Day 5of study treatment
Percentage of subjects achieving clinical recovery	continuous clinical recovery is defined as score (see Appendix 2) of COVID-19 related symptoms ≤ 1 continued for 2 consecutive days or discharge criteria is met. Time of continuous clinical recovery is defined as time (days) between the first initiation of the study treatment devices and the time when the score of relevant COVID-19 related symptoms ≤ 1 continues for 2 consecutive days or discharge criteria is met (whichever comes first).	Day 10 of study treatment
Percentage of subjects achieving clinical recovery	continuous clinical recovery is defined as score (see Appendix 2) of COVID-19 related symptoms ≤ 1 continued for 2 consecutive days or discharge criteria is met. Time of continuous clinical recovery is defined as time (days) between the first initiation of the study treatment devices and the time when the score of relevant COVID-19 related symptoms ≤ 1 continues for 2 consecutive days or discharge criteria is met (whichever comes first).	through study completion, an average of 10 days
Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Day 2 of study treatment
Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Day 3 of study treatment
Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Day 5 of study treatment
Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Day 7 of study treatment
Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Day 10 of study treatment
Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	Percentage of subjects whose WHO Clinical Progression Scale score decreased by 1 point or more	The period from the beginning of treatment in patients enrolled to the time before discharge
Point reduction of WHO Clinical Progression Scale score	Point reduction of WHO Clinical Progression Scale score	Day 2 of study treatment
Point reduction of WHO Clinical Progression Scale score	Point reduction of WHO Clinical Progression Scale score	Day 3 of study treatment
Point reduction of WHO Clinical Progression Scale score	Point reduction of WHO Clinical Progression Scale score	Day 5 of study treatment
Point reduction of WHO Clinical Progression Scale score	Point reduction of WHO Clinical Progression Scale score	Day 7 of study treatment
Point reduction of WHO Clinical Progression Scale score	Point reduction of WHO Clinical Progression Scale score	Day 10 of study treatment
Point reduction of WHO Clinical Progression Scale score	Point reduction of WHO Clinical Progression Scale score	The period from the beginning of treatment in patients enrolled to the time before discharge
Changes in scores of COVID-19 related symptoms	Changes in scores of COVID-19 related symptoms	Day 2 of the study treatment
Changes in scores of COVID-19 related symptoms	Changes in scores of COVID-19 related symptoms	Day 3 of the study treatment
Changes in scores of COVID-19 related symptoms	Changes in scores of COVID-19 related symptoms	Day 5 of the study treatment
Changes in scores of COVID-19 related symptoms	Changes in scores of COVID-19 related symptoms	Day 7 of the study treatment
Changes in scores of COVID-19 related symptoms	Changes in scores of COVID-19 related symptoms	Day 10 of the study treatment
Changes in scores of COVID-19 related symptoms	Changes in scores of COVID-19 related symptoms	The period from the beginning of treatment in patients enrolled to the time before discharge
Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Day 2 of the study treatment
Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Day 3 of the study treatment
Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Day 5 of the study treatment
Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Day 7 of the study treatment
Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Day 10 of the study treatment
Percentage of subjects whose COVID-19 related symptoms have recovered to normal	Percentage of subjects whose COVID-19 related symptoms have recovered to normal	through study completion, an average of 10 days
Total length of hospital stay	Total length of hospital stay	through study completion, an average of 14 days
Time from randomization to conversion to mild type of COVID-19	Time from randomization to conversion to mild type of COVID-19	Time from randomization to conversion to mild type of COVID-19
Oxygen saturation in resting non-oxygen inhalation state	Oxygen saturation will be measured based on finger blood samples in resting state at 10 minutes after stopping the use of the study device for subjects in the test group and the control group	Day 2 of study treatment
Oxygen saturation in resting non-oxygen inhalation state	Oxygen saturation will be measured based on finger blood samples in resting state at 10 minutes after stopping the use of the study device for subjects in the test group and the control group	Day 3 of study treatment
Oxygen saturation in resting non-oxygen inhalation state	Oxygen saturation will be measured based on finger blood samples in resting state at 10 minutes after stopping the use of the study device for subjects in the test group and the control group	Day 5 of study treatment
Oxygen saturation in resting non-oxygen inhalation state	Oxygen saturation will be measured based on finger blood samples in resting state at 10 minutes after stopping the use of the study device for subjects in the test group and the control group	Day 7 of study treatment
Oxygen saturation in resting non-oxygen inhalation state	Oxygen saturation will be measured based on finger blood samples in resting state at 10 minutes after stopping the use of the study device for subjects in the test group and the control group	Day 10 of study treatment
Oxygen saturation in resting non-oxygen inhalation state	Oxygen saturation will be measured based on finger blood samples in resting state at 10 minutes after stopping the use of the study device for subjects in the test group and the control group	through study completion, an average of 10 days
CRP	C-reactive protein	Day 3 of study treatment
CRP	C-reactive protein	Day 7 of study treatment
CRP	C-reactive protein	Day 10 of study treatment
CRP	C-reactive protein	through study completion, an average of 10 days
IL-6	IL-6	Day 3 of study treatment
IL-6	IL-6	Day 7 of study treatment
IL-6	IL-6	Day 10 of study treatment
IL-6	IL-6	through study completion, an average of 10 days
ferritin	ferritin	Day 3 of study treatment
ferritin	ferritin	Day 7 of study treatment
ferritin	ferritin	Day 10 of study treatment
ferritin	ferritin	through study completion, an average of 10 days
lymphocytes	lymphocytes	Day 3 of study treatment
lymphocytes	lymphocytes	Day 7of study treatment
lymphocytes	lymphocytes	Day 10 of study treatment
lymphocytes	lymphocytes	through study completion, an average of 10 days
neutrophil to lymphocyte ratio	neutrophil to lymphocyte ratio	Day 3 of study treatment
neutrophil to lymphocyte ratio	neutrophil to lymphocyte ratio	Day 7 of study treatment
neutrophil to lymphocyte ratio	neutrophil to lymphocyte ratio	Day 10 of study treatment
neutrophil to lymphocyte ratio	neutrophil to lymphocyte ratio	through study completion, an average of 10 days
Percentage of patients with fever, shortness of breath and chest pain all disappeared	Percentage of patients with fever, shortness of breath and chest pain all disappeared	Day 2 of study treatment
Percentage of patients with fever, shortness of breath and chest pain all disappeared	Percentage of patients with fever, shortness of breath and chest pain all disappeared	Day 3 of study treatment
Percentage of patients with fever, shortness of breath and chest pain all disappeared	Percentage of patients with fever, shortness of breath and chest pain all disappeared	Day 5 of study treatment
Percentage of patients with fever, shortness of breath and chest pain all disappeared	Percentage of patients with fever, shortness of breath and chest pain all disappeared	Day 7 of study treatment
Percentage of patients with fever, shortness of breath and chest pain all disappeared	Percentage of patients with fever, shortness of breath and chest pain all disappeared	Day 10 of study treatment
Percentage of patients with fever, shortness of breath and chest pain all disappeared	Percentage of patients with fever, shortness of breath and chest pain all disappeared	through study completion, an average of 10 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of AEs/SAEs	Definition: An AE is defined as any untoward medical occurrence during the course of the clinical trial, whether or not related to the study device. For the definition of SAE	through study completion, an average of 14 days
Incidence of Device Deficiency	Definition: a device deficiency is defined as any inadequacy of a medical device which may pose inappropriate risks to the health or safety of the subjects under normal use of the device during the clinical trial, including inadequate labelling, quality issue, and malfunctions, etc.	through study completion, an average of 14 days

Collaborators and Investigators

• Sponsor: Guangzhou Institute of Respiratory Disease
• Investigators: Principal Investigator: Guan Weijie, PhD, Guangzhou Institute of Respiratory Disease

Publications and helpful links

General Publications

• Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012 Nov 8;367(19):1814-20. doi: 10.1056/NEJMoa1211721. Epub 2012 Oct 17. Erratum In: N Engl J Med. 2013 Jul 25;369(4):394.
• Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B, DeRisi J, Yang JY, Cox N, Hughes JM, LeDuc JW, Bellini WJ, Anderson LJ; SARS Working Group. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003 May 15;348(20):1953-66. doi: 10.1056/NEJMoa030781. Epub 2003 Apr 10.
• Zhou ZQ, Zhong CH, Su ZQ, Li XY, Chen Y, Chen XB, Tang CL, Zhou LQ, Li SY. Breathing Hydrogen-Oxygen Mixture Decreases Inspiratory Effort in Patients with Tracheal Stenosis. Respiration. 2019;97(1):42-51. doi: 10.1159/000492031. Epub 2018 Sep 18.
• 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.
• Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burguiere AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, Muller S, Rickerts V, Sturmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H, Doerr HW. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med. 2003 May 15;348(20):1967-76. doi: 10.1056/NEJMoa030747. Epub 2003 Apr 10.
• de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L, Fouchier RA, Galiano M, Gorbalenya AE, Memish ZA, Perlman S, Poon LL, Snijder EJ, Stephens GM, Woo PC, Zaki AM, Zambon M, Ziebuhr J. Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol. 2013 Jul;87(14):7790-2. doi: 10.1128/JVI.01244-13. Epub 2013 May 15. No abstract available.
• 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.
• Kuiken T, Fouchier RA, Schutten M, Rimmelzwaan GF, van Amerongen G, van Riel D, Laman JD, de Jong T, van Doornum G, Lim W, Ling AE, Chan PK, Tam JS, Zambon MC, Gopal R, Drosten C, van der Werf S, Escriou N, Manuguerra JC, Stohr K, Peiris JS, Osterhaus AD. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet. 2003 Jul 26;362(9380):263-70. doi: 10.1016/S0140-6736(03)13967-0.

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2023
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: February 23, 2023
• First Submitted That Met QC Criteria: March 12, 2023
• First Posted (Actual): March 15, 2023

Study Record Updates

• Last Update Posted (Actual): March 15, 2023
• Last Update Submitted That Met QC Criteria: March 12, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Covid19; Hydrogen-oxygen Gas; AMS-H-03
• 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-03-105

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