Efficacy of oral 20-hydroxyecdysone (BIO101), a MAS receptor activator, in adults with severe COVID-19 (COVA): a randomized, placebo-controlled, phase 2/3 trial.

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.

Efficacy of the adjuvanted subunit protein COVID-19 vaccine, SCB-2019: a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. METHODS: This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). FINDINGS: 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. INTERPRETATION: Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.

Exercise pathophysiology in patients with chronic mountain sickness exercise in chronic mountain sickness.

BACKGROUND: Chronic mountain sickness (CMS) is characterized by a combination of excessive erythrocytosis,severe hypoxemia, and pulmonary hypertension, all of which affect exercise capacity. METHODS: Thirteen patients with CMS and 15 healthy highlander and 15 newcomer lowlander control subjects were investigated at an altitude of 4,350 m (Cerro de Pasco, Peru). All of them underwent measurements of diffusing capacity of lung for nitric oxide and carbon monoxide at rest, echocardiography for estimation of mean pulmonary arterial pressure and cardiac output at rest and at exercise, and an incremental cycle ergometer cardiopulmonary exercise test. RESULTS: The patients with CMS, the healthy highlanders, and the newcomer lowlanders reached a similar maximal oxygen uptake at 32 1, 32 2, and 33 2 mL/min/kg, respectively, mean SE( P 5 .8), with ventilatory equivalents for C O 2 vs end-tidal P CO 2 , measured at the anaerobic threshold,of 0.9 0.1, 1.2 0.1, and 1.4 0.1 mm Hg, respectively ( P , .001); arterial oxygen content of 26 1, 21 2, and 16 1 mL/dL, respectively ( P , .001); diffusing capacity for carbon monoxide corrected for alveolar volume of 155% 4%, 150% 5%, and 120% 3% predicted, respectively( P , .001), with diffusing capacity for nitric oxide and carbon monoxide ratios of 4.7 0.1 at sea level decreased to 3.6 0.1, 3.7 0.1, and 3.9 0.1, respectively ( P , .05) and a maximal exercise mean pulmonary arterial pressure at 56 4, 42 3, and 31 2 mm Hg, respectively ( P , .001). CONCLUSIONS: The aerobic exercise capacity of patients with CMS is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume.

Pulmonary capillary blood volume and membrane conductance in Andeans and lowlanders at high altitude: a cross-sectional study.

Lung carbon monoxide (CO) transfer and pulmonary capillary blood volume (Vc) at high altitudes have been reported as being higher in native highlanders compared to acclimatised lowlanders but large discrepancies appears between the studies. This finding raises the question of whether hypoxia induces pulmonary angiogenesis. Eighteen highlanders living in Bolivia and 16 European lowlander volunteers were studied. The latter were studied both at sea level and after acclimatisation to high altitude. Membrane conductance (Dm(CO)) and Vc, corrected for the haemoglobin concentration (Vc(cor)), were calculated using the NO/CO transfer technique. Pulmonary arterial pressure and left atrial pressures were estimated using echocardiography. Highlanders exhibited significantly higher NO and CO transfer than acclimatised lowlanders, with Vc(cor)/VA and Dm(CO)/VA being 49 and 17% greater (VA: alveolar volume) in highlanders, respectively. In acclimatised lowlanders, Dm(CO) and Dm(CO)/VA values were lower at high altitudes than at sea level. Echocardiographic estimates of cardiac output and pulmonary arterial pressure were significantly elevated at high altitudes as compared to sea level. The decrease in Dm(CO) in lowlanders might be due to altered gas transport in the airways due to the low density of air at high altitudes. The disproportionate increase in Vc in Andeans compared to the change in Dm(CO) suggests that the recruitment of capillaries is associated with a thickening of the blood capillary sheet. Since there was no correlation between the increase in Vc and the slight alterations in haemodynamics, this data suggests that chronic hypoxia might stimulate pulmonary angiogenesis in Andeans who live at high altitudes.

Echocardiographic and tissue Doppler imaging of cardiac adaptation to high altitude in native highlanders versus acclimatized lowlanders.

High-altitude exposure is a cause of pulmonary hypertension and decreased exercise capacity, but associated changes in cardiac function remain incompletely understood. The aim of this study was to investigate right ventricular (RV) and left ventricular function in acclimatized Caucasian lowlanders compared with native Bolivian highlanders at high altitudes. Standard echocardiography and tissue Doppler imaging studies were performed in 15 healthy lowlanders at sea level; <24 hours after arrival in La Paz, Bolivia, at 3,750 m; and after 10 days of acclimatization and ascent to Huayna Potosi, at 4,850 m, and the results were compared with those obtained in 15 age- and body size-matched inhabitants of Oruro, Bolivia, at 4,000 m. Acute exposure to high altitude in lowlanders caused an increase in mean pulmonary arterial pressure, to 20 to 25 mm Hg, and altered RV and left ventricular diastolic function, with prolonged isovolumic relaxation time, an increased RV Tei index, and maintained RV systolic function as estimated by tricuspid annular plane excursion and the tricuspid annular S wave. This profile was essentially unchanged after acclimatization and ascent to 4,850 m, except for higher pulmonary arterial pressure. The native highlanders presented with relatively lower pulmonary arterial pressures but more pronounced alterations in diastolic function, decreased tricuspid annular plane excursion and tricuspid annular S waves, and increased RV Tei indexes. In conclusion, cardiac adaptation to high altitude was qualitatively similar in acclimatized Caucasian lowlanders and in Bolivian native highlanders. However, lifelong exposure to high altitude may be associated with different cardiac adaptation to milder hypoxic pulmonary hypertension.