Molecular Hydrogen for Outpatients with COVID-19 (Hydro-COVID): A Phase 3 Randomised, Triple-Blinded, Pragmatic, Placebo-Controlled, Multicentre Trial
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Participants
2.3. Randomisation and Masking
2.4. Interventions
2.5. Outcomes
2.6. Safety
2.7. Statistical Analysis
3. Results
3.1. Participants
3.2. Efficacy
3.3. Safety
4. Discussion
4.1. Summary
4.2. Strengths and Limitations
4.3. Comparison with Existing Literature
4.4. Implications for Research and/or Practice
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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H2 (n = 337) | Placebo (n = 338) | p-Value | |||
---|---|---|---|---|---|
Country, no. (%) | 0.96 | ||||
France | 210 (62.3) | 210 (62.1) | |||
Serbia | 127 (37.7) | 128 (37.9) | |||
Median age, [IQR], yr | 57 [46–64] | 57 [49–64] | 0.25 | ||
Age group, no (%) | 0.11 | ||||
<50 yr | 114 (33.8) | 93 (27.5) | |||
50–59 yr | 83 (24.6) | 110 (32.5) | |||
60–69 yr | 103 (30.6) | 99 (29.3) | |||
≥70 yr | 37 (11.0) | 36 (10.7) | |||
Sex at birth, no (%) | 0.85 | ||||
Female | 206 (61.1) | 209 (61.8) | |||
Male | 131 (38.9) | 129 (38.1) | |||
Risk factors for severe COVID-19, no. (%) | |||||
Obesity * | 95 (28.2) | 98 (29.0) | 0.82 | ||
Body mass index > 35 kg/m2 | 27 (8.0) | 32 (9.5) | 0.5 | ||
Diabetes mellitus | 31 (9.2) | 35 (10.4) | 0.61 | ||
Serious heart condition † | 12 (3.6) | 13 (3.9) | 0.84 | ||
Serious respiratory condition ‡ | 28 (8.3) | 26 (7.7) | 0.77 | ||
Chronic kidney disease (Clearance < 60 mL/min/1.73 m2) | 3 (0.9) | 3 (0.9) | 1 | ||
Active Cancer | 3 (0.9) | 4 (1.2) | 1 | ||
Association between three non major risk factors | 34 (10.1) | 36 (10.7) | 0.81 | ||
Co-existing conditions | |||||
Tabagism | 58 (17.2) | 60 (17.8) | 0.85 | ||
Hypertension | 135 (40.1) | 142 (42.0) | 0.61 | ||
Dyslipidemia | 35 (10.4) | 37 (11.0) | 0.81 | ||
Asthma | 26 (7.7) | 22 (6.5) | 0.54 | ||
Medications at baseline | |||||
Corticotherapy | 13 (3.9) | 6 (1.8) | 0.1 | ||
Anticoagulation | 12 (3.6) | 11 (3.3) | 0.83 | ||
Non-steroidal anti-inflammatory drugs | 31 (9.2) | 36 (10.7) | 0.53 | ||
Quality of life (EQ5D Index score), median [IQR] | 0.95 [0.88–0.97] | 0.95 [0.9–0.98] | 0.99 | ||
Quality of life (EQ5-VAS), median [IQR] | 65 [50–80] | 65 [50–80] | 0.83 | ||
Quality of sleep (PSQI) | 5 [3–8] | 5 [3–8] | 0.77 | ||
Patient vaccinated against SARS-CoV-2, no. (%) | 249 (73.9) | 235 (69.5) | 0.21 | ||
Theorical variant designation ¶, n (%) | 0.69 | ||||
Alpha | 25 (7.4) | 31 (9.2) | |||
Delta | 182 (54.0) | 176 (52.1) | |||
Omicron | 130 (38.6) | 131 (38.8) | |||
Time since first symptoms to randomization ‖, no. (%) | n = 316 | n = 307 | 0.65 | ||
≤3 days | 217 (68.7) | 216 (70.4) | |||
>3 days | 99 (31.3) | 91 (29.6) | |||
Number of different symptoms in the initial phase, no. (%) | |||||
1 | 12 (3.6) | 15 (4.4) | 0.92 | ||
2 | 50 (14.8) | 51 (15.1) | |||
3 | 71 (21.1) | 76 (22.5) | |||
4 | 80 (23.7) | 82 (24.3) | |||
>4 | 124 (36.8) | 114 (22.7) |
H2 (n: 334) | Placebo (n: 333) | p-Value | |||
---|---|---|---|---|---|
Number (percent) | |||||
Primary endpoint * | |||||
Clinical deterioration at day 14 | 154 (46.1) | 145 (43.5) | 0.479 | ||
Physical fatigue | 99 (29.4) | 88 (26.4) | 0.383 | ||
Chalder scale | 4 (1.2) | 3 (0.9) | |||
On a visual analogic scale | 37 (11.1) | 31 (9.3) | |||
Described by the patient | 68 (20.4) | 61 (18.3) | |||
Mental symptoms | 46 (13.8) | 54 (16.2) | 0.391 | ||
Chalder scale | 5 (1.5) | 7 (2.1) | |||
On a visual analogic scale | 42 (12.6) | 47 (14.1) | |||
Breathlessness | 78 (23.4) | 67 (23.1) | 0.31 | ||
On mMRC | 17 (5.1) | 14 (4.2) | |||
On a visual analogic scale | 44 (13.2) | 43 (12.9) | |||
Described by the patient | 32 (9.6) | 23 (6.9) | |||
Hospitalisation/Oxygen therapy required | 11 (3.3) | 10 (3.0) | 0.83 | ||
Death | 1 (0.3) | 0 | |||
Secondary end points | |||||
Age (yr) | 0.6 | ||||
<50 | 48 (42.5) | 36 (40.9) | |||
50–59 | 45 (54.9) | 51 (46.4) | |||
60–69 | 39 (38.2) | 41 (41.4) | |||
≥70 | 22 (59.5) | 17 (47.2) | |||
Sex at birth, no (%) | 0.73 | ||||
Female | 107 (52.5) | 99 (48.3) | |||
Male | 47 (36.2) | 46 (35.9) | |||
Hospitalisation/Oxygen therapy required at Day-30 | 12 (2.6) | 10 (3.0) | 0.83 | ||
Death at Day-30 | 1 (0.3) | 2 (0.6) | 0.58 | ||
Treatment compliance at day 14 | |||||
≥80% | 252 (76.8) | 263 (80.7) | 0.252 | ||
≥50% | 272 (82.9) | 284 (87.1) | 0.154 | ||
Treatment compliance at day 21 | n: 229 | n: 248 | |||
≥80% | 197 (86.0) | 211 (85.1) | 0.796 | ||
≥50% | 217 (94.8) | 234 (94.4) | 1 | ||
Quality of life (index score), at day-30 median [IQR] | 0.98 (0.93–0.1) | 0.98 (0.93–0.1) | 0.212 | ||
Quality of life (health status) at day-30 median [IQR] | 80 (70–90) | 80 (70–90) | 0.76 | ||
Quality of sleep, median [IQR] | 5 (3–8.7) | 5 (3.5–7) | 0.047 |
Adverse Event Category | H2 (n = 337) | Placebo (n = 338) | p-Value | |
---|---|---|---|---|
Events that emerged during treatment period | ||||
Patients with adverse events—no. (%) | 91 (27.0) | 89 (26.2) | 0.84 | |
Any adverse event | 126 (37.4) | 124 (36.7) | 0.85 | |
Serious adverse event | 21 (6.2) | 27 (8.0) | 0.79 | |
Maximum grade 3 or 4 adverse events | 7 (2.1) | 11 (3.3) | 0.34 | |
Maximum grade 5 adverse event | 1 | 2 | 1 | |
Discontinued drug or placebo because of an adverse event | 16 (4.7) | 14 (4.1) | 0.85 | |
Had a dose reduction or temporary discontinuation owing to an adverse event | 2 | 3 | 1 | |
Events considered to be related to drug or placebo | ||||
Patients with adverse events—no. (%) | 60 (17.8) | 59 (17.5) | 0.9 | |
Any adverse event | 76 (22.6) | 74 (21.9) | 0.84 | |
Serious adverse event | 1 | 0 | 1 | |
Maximum grade 3 or 4 adverse events | 1 | 0 | 1 | |
Maximum grade 5 adverse event | 0 | 0 | 1 | |
Discontinued drug or placebo because of an adverse event | 4 (1.2) | 5 (1.5) | 0.6 | |
Had a dose reduction or temporary discontinuation owing to an adverse event | 23 (6.8) | 21 (6.2) | 0.75 |
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Share and Cite
Gaboreau, Y.; Milovančev, A.; Rolland, C.; Eychenne, C.; Alcaraz, J.-P.; Ihl, C.; Mazet, R.; Boucher, F.; Vermorel, C.; Ostojic, S.M.; et al. Molecular Hydrogen for Outpatients with COVID-19 (Hydro-COVID): A Phase 3 Randomised, Triple-Blinded, Pragmatic, Placebo-Controlled, Multicentre Trial. J. Clin. Med. 2024, 13, 4308. https://doi.org/10.3390/jcm13154308
Gaboreau Y, Milovančev A, Rolland C, Eychenne C, Alcaraz J-P, Ihl C, Mazet R, Boucher F, Vermorel C, Ostojic SM, et al. Molecular Hydrogen for Outpatients with COVID-19 (Hydro-COVID): A Phase 3 Randomised, Triple-Blinded, Pragmatic, Placebo-Controlled, Multicentre Trial. Journal of Clinical Medicine. 2024; 13(15):4308. https://doi.org/10.3390/jcm13154308
Chicago/Turabian StyleGaboreau, Yoann, Aleksandra Milovančev, Carole Rolland, Claire Eychenne, Jean-Pierre Alcaraz, Cordelia Ihl, Roseline Mazet, François Boucher, Celine Vermorel, Sergej M. Ostojic, and et al. 2024. "Molecular Hydrogen for Outpatients with COVID-19 (Hydro-COVID): A Phase 3 Randomised, Triple-Blinded, Pragmatic, Placebo-Controlled, Multicentre Trial" Journal of Clinical Medicine 13, no. 15: 4308. https://doi.org/10.3390/jcm13154308
APA StyleGaboreau, Y., Milovančev, A., Rolland, C., Eychenne, C., Alcaraz, J.-P., Ihl, C., Mazet, R., Boucher, F., Vermorel, C., Ostojic, S. M., Borel, J.-C., Cinquin, P., & Bosson, J.-L. (2024). Molecular Hydrogen for Outpatients with COVID-19 (Hydro-COVID): A Phase 3 Randomised, Triple-Blinded, Pragmatic, Placebo-Controlled, Multicentre Trial. Journal of Clinical Medicine, 13(15), 4308. https://doi.org/10.3390/jcm13154308