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Cited by 27COVID-19 Clinical Research StudiesRenin-Angiotensin System StudiesSARS-CoV-2 and COVID-19 Research

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

Open access
Lobo, Suzana Margareth, Plantefève, Gaétan, Nair, Girish, Joaquim Cavalcante, Adilson, Franzin de Moraes, Nara, Nunes, Estevao, Barnum, Otis, Berdun Stadnik, Claudio Marcel +43 more·2024·eClinicalMedicine
DOI 10.1016/j.eclinm.2023.102383PMC PMC10965409
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Abstract

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.

AI snapshot

Written from the paper’s full text.

TL;DR

In adults hospitalized with severe COVID-19, oral BIO101 (20-hydroxyecdysone) 350 mg BID significantly reduced the composite of death or respiratory failure by day 28 versus placebo in the modified ITT population. Discharge and mortality outcomes numerically favored BIO101 but were not statistically significant.

Key findings

  • Primary endpoint: first negative event (death or respiratory failure requiring mechanical ventilation, ECMO, or high-flow oxygen per protocol) by day 28 occurred in 13.5% of BIO101 patients vs. 24.3% of placebo patients; adjusted difference −11.4% (95% CI −22.4% to −0.4%), p = 0.0426, with a 43.8% relative risk reduction and number needed to treat of 9.
  • Key secondary endpoint: hospital discharge following recovery by day 28 was 80.1% with BIO101 vs. 70.9% with placebo; adjusted difference 11.0% (95% CI −0.4% to 22.4%), p = 0.0586.
  • Mortality: day 28 death from any cause was 7.9% vs. 14.0% (adjusted difference −6.2%, 95% CI −14.5% to 2.2%, nominal p = 0.1476); 90-day hazard ratio for time to death was 0.554 (95% CI 0.285–1.077), a 44.6% mortality reduction that was not statistically significant.
  • Safety: any TEAE occurred in 57.0% of BIO101 patients vs. 64.4% of placebo patients; serious TEAEs in 25.0% vs. 30.8%; respiratory failure TEAEs in 9.4% vs. 18.3%.

Methods

  • Double-blind, randomized, placebo-controlled phase 2/3 trial; 1:1 oral BIO101 350 mg BID or placebo up to 28 days or until a predefined endpoint; 37 sites in Brazil, the United States, France, and Belgium; enrollment from August 26, 2020 to March 8, 2022, halted early due to low recruitment.
  • 238 patients were randomized; the modified ITT population included 233 patients (126 BIO101, 107 placebo) after excluding 5 who received no study medication and had no efficacy data. Primary endpoint was death or respiratory failure requiring mechanical ventilation, ECMO, or high-flow oxygen (HFO2 until protocol V12); key secondary endpoint was hospital discharge following recovery.
  • Primary and key secondary analyses used the Cochran-Mantel-Haenszel test stratified by RAS pathway modulator use, gender, comorbidities, and CPAP/BiPAP/HFO2 at entry, with placebo-based multiple imputation for missing data; sensitivity analyses included logistic regression, Kaplan-Meier estimates, and Cox models.

Limitations

  • The paper states the trial was designed and launched early in the pandemic: SARS-CoV-2 variant and vaccine status were not collected, standard of care evolved during enrollment, and the trial was terminated after 238 patients instead of the planned 310.
  • The paper also notes baseline imbalances, including more immunosuppressant use in the placebo group and a higher proportion of males in the BIO101 group, which may explain why some secondary endpoints did not reach statistical significance.
  • Evident from the text: the primary endpoint definition changed with protocol V12 regarding HFO2, and the key secondary discharge endpoint and mortality endpoints were not statistically significant despite numerical differences favoring BIO101.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.eclinm.2023.102383

Cites

33 of 33 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 44 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The relative risk of having negative events was reduced by 43.8% in the BIO101 arm.

    “The RR of having negative events was reduced by 43.8% in the BIO101 arm.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the modified intention-to-treat population, BIO101 reduced the primary outcome of death or respiratory failure by day 28 compared with placebo (13.5% vs 24.3%; adjusted difference −11.4%, 95% CI −22.4% to −0.4%; p=0.0426).

    “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).”
    • Also stated in: § Primary outcome · plain
      “In the mITT population, using the CMH test with multiple imputation for missing data, the first negative event rate was statistically significantly lower in the BIO101 group than in the placebo group (adjusted difference: −11.4% [95% CI: −22.4%, −0.4%]; p = 0.0426)”
    • Also stated in: § Funding · plain
      “Compared to placebo, BIO101 significantly lowers the proportion of patients experiencing respiratory failure or early death by day 28.”
    Quote in the paperSubstantial claim
  • Findingown data

    Benefits of BIO101 were confirmed by sensitivity analyses: logistic regression odds ratio 0.47 (95% CI 0.23-0.95) and Kaplan-Meier difference 10.9% (95% CI 0.6-21.2).

    “Benefits of BIO101 were confirmed by sensitivity analyses by logistic regression of all negative events by day 28 (odds ratio (OR) of 0.47 (95% CI: 0.23, 0.95)) and by Kaplan–Meier proportions (difference 10.9%, 95% CI [0.6%, 21.2%]) (Fig. 2A).”
    Quote in the paperSubstantial claim
  • Findingown data

    In adults with severe COVID-19, BIO101 350 mg BID did not significantly increase the proportion of patients discharged from hospital due to improvement at day 28 compared with placebo (80.1% vs 70.9%; adjusted difference 11.0%, 95% CI −0.4 to 22.4, p=0.0568).

    “The proportion of subjects discharged from hospital due to improvement (positive events) at day 28 was numerically higher in the BIO101 group (80.1%) than in the placebo group (70.9%) although this difference did not reach statistical significance (adjusted difference: 11.0% [95% CI: −0.4%, 22.4%], p = 0.0568) (Table 2A).”
    • Also stated in: § Primary outcome · plain
      “Key secondary endpointbProportion of patients discharged from hospital due to improvement. (First positive events) | 100.94 (80.1) | 75.91 (70.9) | 9.2 | 11.0 (−0.4, 22.4) | 0.0586”
    Quote in the paperSubstantial claim
  • Findingown data

    Treatment emergent adverse events of respiratory failure were more frequent in the placebo group than in the BIO101 group.

    “Treatment emergent adverse events of respiratory failure were more frequent in the placebo group.”
    • Also stated in: § Funding · plain
      “although respiratory failure events were more frequent in the placebo group.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 30
  • Classified as probably not a substantial claim. 26

  • May combine two claims.

    Findingown data

    Treatment effects on the primary endpoint were not meaningfully different in subgroup categories, and all odds ratios were in favour of BIO101.

    “Treatment effects on the primary endpoint were not meaningfully different in subgroup categories. All ORs were in favour of BIO101, and the consistent beneficial effect of BIO101 was further confirmed by these analyses (Supplementary Figure S1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Treatment effects were numerically different between the France/Belgium/US subgroup (adjusted difference −0.14%, 95% CI −23.3% to 23.0%) and the Brazil subgroup (adjusted difference −12.1%, 95% CI −25.7% to 1.6%), but overlapping confidence intervals provide no evidence for a differential treatment effect across regions.

    “Treatment effects were numerically different between the France, Belgium, and US subgroup (adjusted difference −0.14%, 95% CI [−23.3%, 23.0%]), and the Brazil subgroup (adjusted difference: −12.1%, 95% CI [−25.7%, 1.6%]) (Supplementary Figure S3), but as the confidence intervals are substantially overlapping there is no evidence for a differential treatment effect across regions.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The populations recruited in Belgium and the USA are comparable to the population recruited in France, justifying merging them for subgroup analysis.

  • May combine two claims.

    Findingown data

    At day 28, the proportion of patients who died was lower in BIO101 than placebo, but the difference did not reach statistical significance.

    “The proportion of patients recovered was higher in the BIO101 group than placebo and the proportion of patients who died was lower, however these differences did not reach statistical significance.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: In the day-28 mortality analysis, patients with missing outcomes were assumed to have survived.

  • May combine two claims.

    Findingown data

    The hazard ratio for time to death over 90 days was 0.554 (95% CI 0.285-1.077), a 44.6% mortality reduction in the BIO101 group, not statistically significant.

    “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).”
    • Also stated in: § Funding · plain
      “The proportion of patients recovered was higher in the BIO101 group than placebo and the proportion of patients who died was lower, however these differences did not reach statistical significance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The observed effect of BIO101 on the primary endpoint was slightly larger than originally expected in the sample size estimation (37.5%).

    “an effect slightly larger than originally expected in the sample size estimation (37.5%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BIO101 (20-hydroxyecdysone) is a non-peptidic Mas receptor activator that reduces the severity of lung injury induced by intratracheal lipopolysaccharide in mice.

    “BIO101 (20-hydroxyecdysone (20E)), is a non-peptidic MasR activator that reduces the severity of lung injury induced by an intratracheal instillation of lipopolysaccharide in mice.”
    • Also stated in: § Introduction · plain
      “Biophytis is developing BIO101, a pharmaceutical grade formulation of 20-Hydroxyecdysone (20E), which is a MasR activator24 that reduces the severity of lung injury induced by an intratracheal instillation of lipopolysaccharide in mice.25”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Lafont, 2021, 20-Hydroxyecdysone activates the protective arm of the RAAS via the MAS receptor, J Mol Endocrinol source

      Not checked in the free run.

    • cites [25] Song, 2019, Protective effect of 20-hydroxyecdysterone against lipopolysaccharides-induced acute lung injury in mice, J Pharm Drug Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The phase 2 improvement with C21 was not confirmed in phase 3, and recent clinical trials testing TRV-027 and TXA-127 did not show clinical improvement in this patient population.

    “but these observations were not confirmed in phase 3, and recently clinical trials testing this therapeutic approach using a biased agonist of AT1R (TRV-027) and a synthetic Angiotensin-1-7 (TXA-127) did not show clinical improvement in this patient population.23”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Self, 2023, Renin-angiotensin system modulation with synthetic angiotensin (1-7) and angiotensin II type 1 receptor-biased ligand in adults with COVID-19: two randomized clinical trials, JAMA source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A total of 238 subjects were randomized: 129 to BIO101 and 109 to placebo.

    “There were 238 subjects randomized: (129 assigned to BIO101 and 109 receiving placebo).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Randomization was stratified for RAS pathway modulator use and comorbidities in Part 1, and additionally by center, gender, and use of CPAP/BiPAP/HFO2 in Part 2.

    “In Part 1 of the study, randomization was stratified for RAS pathway modulators use and comorbidities (no vs. ≥1) only. In Part 2, randomization was additionally stratified by center, gender, and use of CPAP/BiPAP/HFO2 (Yes/No/Missing).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Sensitivity analyses were conducted to evaluate the robustness of the primary endpoint results, including excluding HFO2 from the primary endpoint definition.

    “Sensitivity analyses were conducted to evaluate the robustness of the results for the primary endpoint including requiring HFO2 excluded from the definition of the primary endpoint.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Baseline characteristics were well balanced between groups, including age, comorbidities, oxygen supplementation, and SARS-CoV-2 viral load.

    “The mean age of the global population was 62.8 years (SD 9.21 years) and was not different between the placebo and BIO101 groups.”
    • Also stated in: § Results · boosted
      “Most patients had at least one (92.3%) coexisting condition at enrollment, which were well balanced between the two groups”
    • Also stated in: § Results · plain
      “Importantly, at enrolment the percentages of patients needing oxygen supplementation were equivalent and SARS-CoV-2 viral load were similar in both groups.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A total of 13 (5.6%) subjects were reported to have at least 1 major protocol deviation.

    “A total of 13 (5.6%) subjects were reported to have at least 1 major protocol deviation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    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.

    “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.”
    • Also stated in: § Study design and participants · plain
      “Enrollment began on August 26, 2020, and ended on March 8, 2022 following sponsor decision to halt the study due to low recruitment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    A total of 194 (83.3%) subjects in the modified intention-to-treat analysis group completed study treatment, and 39 (16.7%) discontinued treatment.

    “A total of 194 (83.3%) subjects in the mITT analysis group completed the study treatment. Thirty-nine subjects (16.7%) discontinued from study treatment, the reasons being: AE/SAE (24 [10.3%] subjects), other/unspecified reasons (8 [3.4%] subjects), withdrawal of consent (6 [2.6%] subjects), and noncompliance of 1 subject (0.4%) (Fig. 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Other secondary endpoints were not controlled for multiplicity and only descriptive statistics and 95% confidence intervals are provided, except mortality at day 28 where the p-value is nominal.

    “Other secondary endpoints were not controlled for multiplicity and only descriptive statistics and 95% confidence (CI) intervals for treatment differences are provided except in the case of mortality at day 28 where the p-value is presented as “nominal”.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Multiplicity was controlled by evaluating the key secondary endpoint only if the primary endpoint was statistically significant.

    “Multiplicity was controlled by evaluating the key secondary endpoint only if the primary endpoint gave a statistically significant result.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Overall, 92.7% of patients achieved 80-100% treatment compliance, and total doses, mean daily doses, and mean days on treatment were similar between arms.

    “Overall, 92.7% of patients achieved 80–100% treatment compliance and the total number of doses administered, mean daily doses and the mean number of days on treatment (BIO101; 8.9 ± 6.13 days vs. Placebo; 7.6 ± 5.36 days) were similar between treatment arms (Supplementary Table S1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The study was a double-blind, randomized, placebo-controlled, group sequential phase 2/3 trial in 2 parts.

    “Double-blind, randomized, placebo-controlled phase 2/3 trial.”
    • Also stated in: § Study design and participants · plain
      “This was a double-blind, placebo-controlled, group sequential study in 2 parts.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Age and immunosuppressant usage at baseline were included as covariates because of clinical relevance and observed imbalance between treatment arms.

    “Age and immunosuppressants usage at baseline were included as additional covariates in the model because of their clinical relevance (age) and due to the observed imbalance of immunosuppressants usage at baseline between treatment arms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Three subjects in the BIO101 group and 2 in the placebo group did not receive study medication and were excluded from the modified intention-to-treat analysis set, leaving 233 patients.

    “From these, consistent with ITT principles, three subjects in the BIO101 group and 2 in the placebo group that did not receive any study medication were not included in the mITT analysis set (n = 233).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Primary analysis used the Cochran-Mantel-Haenszel test stratified by RAS pathway modulator use, gender, comorbidities, and CPAP/BiPAP/HFO2 at study entry, with placebo-based multiple imputation for missing data.

    “Primary analysis of the primary endpoint and of the key secondary endpoint were performed using the Cochran-Mantel-Haenszel (CMH) test stratified by RAS pathway modulator use (Yes/No), gender, co-morbidities (no vs. ≥1) and receiving CPAP/BiPAP/HFO2 at study entry (Yes/No/Missing)”
    • Also stated in: § Statistical analysis · plain
      “and with placebo-based multiple imputation for missing data (3 [1.3%] subjects) based on an imputation model that included the stratification factors, fitted to data for placebo subjects only.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Participants, investigators, and the sponsor were kept blind to treatment allocation.

    “During the study, the participants, investigators, and the sponsor were kept blind to which treatments arms each patient was allocated.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The trial protocol was approved by national regulatory agencies and institutional review boards, and written informed consent was obtained from each patient or their legally authorized representative.

    “The trial protocol was approved by national regulatory agencies in each country and by institutional review board at each site or by a centralized national ethics committee. Written informed consent was obtained from each patient or from their legally authorized representative if the patient was unable to provide consent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Initial sample size was 310 patients, giving 80% power to detect a 15% absolute difference in the primary endpoint, estimated at 40% in placebo and 25% in BIO101, corresponding to a 37.5% relative risk reduction.

    “Initial sample size was 310 patients which gave the study 80% power to detect a 15% absolute difference in proportion of subjects with primary endpoint (negative events), estimated at 40% in the placebo group and 25% in the BIO101 group, corresponding to a 37.5% relative risk (RR) reduction.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Data management and statistical analyses were done in a masked manner by a Contract Research Organization paid by the funding source.

    “Data management and statistical analyses were done in a masked manner by a Contract Research Organization paid by the funding source.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Immunosuppressants were used more frequently in the placebo group (9 subjects, 8.4%) than in the BIO101 group (4 subjects, 3.2%).

    “During the study, concomitant medications including corticosteroids usage were also equally distributed except immunosuppressants (mainly baricitinib and tocilizumab) which were used more frequently in the placebo group (9 subjects, [8.4%]) than in the BIO101 group (4, [3.2%]) (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The report is based on final protocol version 13.0 and final SAP version 1.0 dated 06 May 2022, finalized prior to unblinding.

    “This report is based on the final protocol version 13.0, and the final SAP version 1.0, dated 06 May, 2022 that was finalized prior to unblinding.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    BIO101 significantly reduced the risk of death or respiratory failure, supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19.

    “BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Because BIO101 does not interfere with AT1R like TRV-027, the positive results in COVID-19 suggest a particular importance of MasR activation in the regulation of respiratory function.

    “Because BIO101 does not interfere with AT1R like TRV-027, our positive results in COVID-19 perhaps suggest a particular importance of MasR activation in the regulation of respiratory function.28”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Fournier, 2012, Emergence and evolution of the renin-angiotensin-aldosterone system, J Mol Med (Berl) source

      Not checked in the free run.

    • Rests on an assumption: BIO101 does not interfere with AT1R like TRV-027.

  • May combine two claims.

    Interpretationown data

    The safety profile of BIO101 in COVID-19 patients was favorable, with similar proportions of patients with any TEAEs in the BIO101 group compared to placebo and lower frequencies of respiratory failure events.

    “The safety profile of BIO101 in COVID-19 patients was favorable with similar proportions of patients with any TEAEs in the BIO101 group compared to placebo (73 [57.0%] vs. 67 [64.4%]) and lower frequencies of respiratory failure events.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ang-1-7's half-life in humans is approximately half an hour, shorter than BIO101's half-life of 2.4 to 4.9 hours.

    “In addition, Ang-1-7's half-life in humans is approximately half an hour31 and is shorter compared to BIO101's half-life (2.4 h–4.9 h).32”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Rodgers, 2006, Phase I/II dose escalation study of angiotensin 1-7 [A(1-7)] administered before and after chemotherapy in patients with newly diagnosed breast cancer, Cancer Chemother Pharmacol source

      Not checked in the free run.

    • cites [32] Dioh, 2023, A Phase 1 study for safety and pharmacokinetics of BIO101 (20-hydroxyecdysone) in healthy young and older adults, J Cachexia Sarcopenia Muscle source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    An association between BIO101 and increase in gamma-glutamyl-transferase cannot be excluded but seems unlikely.

    “An association between BIO101 and increase in gamma-glutamyl-transferase cannot be excluded but seems unlikely (Supplementary Table S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    There was a higher proportion of patients using immunosuppressants in the placebo group and a higher proportion of males in the BIO101 group.

    “but also the higher proportion of patients using immunosuppressants in the placebo group, and the higher proportion of males in the BIO101 group”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    All these elements could explain the differences in efficacy of BIO101 and TXA-127 on COVID-19 respiratory symptoms and mortality.

    “All these elements could explain the differences in efficacy of BIO101 and TXA-127 on COVID-19 respiratory symptoms and mortality.23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Self, 2023, Renin-angiotensin system modulation with synthetic angiotensin (1-7) and angiotensin II type 1 receptor-biased ligand in adults with COVID-19: two randomized clinical trials, JAMA source

      Not checked in the free run.

    • Rests on an assumption: Ang-1-7 is cleaved into several peptides (Ang-1-5, Ang-1-4, and others) that are susceptible to evoke different biological effects.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Approximately half of the patients included in the mITT analysis were hypertensive, and this proportion was similar in the BIO101 and placebo groups.

    “In the COVA study (as in previous studies4,5), approximately half of the patients included in the mITT analysis were hypertensive, and this proportion was similar in the BIO101 and the placebo groups (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The vaccine status of the patients included in the COVA study was not collected.

    “Similarly, early in 2020 the commercialization of a vaccine was highly hypothetical, therefore the vaccine status of the patients included in the COVA study was not collected either.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Male gender is a risk factor for severe COVID-19.

    “(male gender being a risk factor for severe COVID-192,33)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Gupta, 2020, Factors associated with death in critically ill patients with coronavirus disease 2019 in the US, JAMA Intern Med source

      Not checked in the free run.

    • cites [33] Peckham, 2020, Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission, Nat Commun source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Due to BIO101's mode of action through activation of the MasR, viral strains are not anticipated to influence BIO101's effects.

    “However, due to BIO101's mode of action through activation of the MasR, it is anticipated that viral strains would not influence BIO101's effects.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Restoring RAS balance either by inhibition of the classical arm or by stimulation of the protective arm would benefit patients with severe respiratory symptoms associated with COVID-19.

    “Therefore, it has been suggested that restoring RAS balance either by inhibition of the classical arm of the RAS (ACE/Ang-II/AT1R) with classical ACE inhibitors or AT1R blockers (ARBs) or alternatively by stimulation of the protective arm of the RAS (ACE2/angiotensin 1-7/MasR axis) with AT2R or MasR activators would benefit patients with severe respiratory symptoms associated with COVID-19.18”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Latil, 2021, Developing new drugs that activate the protective arm of the renin-angiotensin system as a potential treatment for respiratory failure in COVID-19 patients, Drug Discov Today source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    Binding of SARS-CoV-2's spike protein to ACE2 may lead to dysregulation of the RAS.

    “we and others have posed the hypothesis that binding of SARS-CoV-2's spike protein to ACE2 may lead to a dysregulation of the RAS.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Sarzani, 2020, Disequilibrium between the classic renin-angiotensin system and its opposing arm in SARS-CoV-2-related lung injury, Am J Physiol Lung Cell Mol Physiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationown data

    These results support further investigation of BIO101 as a treatment for patients hospitalized with severe pneumonia due to COVID-19.

    “These results support the clinical relevance of RAS modulation through activation of the MASR for treating COVID-19 and support further investigation on the use of BIO101 as treatment for patients hospitalized with severe pneumonia due to COVID-19.30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Dinan, 2021, 20-Hydroxyecdysone, from plant extracts to clinical use: therapeutic potential for the treatment of neuromuscular, cardio-metabolic and respiratory diseases, Biomedicines source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    C21 (an activator of the AT2R) improved respiratory function in patients with severe COVID-19.

    “early in the pandemic it has been reported that C21 (an activator of the AT2R) improved respiratory function in patients with severe COVID-19,22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Tornling, 2021, Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial, eClinicalMedicine source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Early termination, higher proportion of immunosuppressant use in placebo, and higher proportion of males in BIO101 may explain the absence of statistically significant effects of BIO101 on some secondary endpoints.

    “All those factors may also explain the absence of statistically significant effects of BIO101 on some secondary endpoints such as the proportion of patients discharged from hospital or death at Day 28, despite numerical difference in favour of BIO101 treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Benefits of BIO101 were confirmed by logistic regression (OR: 0.47), by subgroup analysis, and by Kaplan-Meier analysis of time to negative event over 28 days.

    “Benefits of BIO101 were confirmed by logistic regression (OR: 0.47), by subgroup analysis, and by Kaplan–Meier analysis of time to negative event over 28 days.”
    Quote in the paperSubstantial claim
44 of 44

  • The authors state this as an assumption.

    In the day-28 mortality analysis, patients with missing outcomes were assumed to have survived.

    “In this analysis patients with missing outcomes were assumed to have survived.”

  • The paper relies on this without support.

    The populations recruited in Belgium and the USA are comparable to the population recruited in France, justifying merging them for subgroup analysis.

    “since the number of patients recruited in Belgium and USA were low, we merged them with patients recruited in France as we estimated that the populations would likely be comparable.”

  • The paper relies on this without support.

    Ang-1-7 is cleaved into several peptides (Ang-1-5, Ang-1-4, and others) that are susceptible to evoke different biological effects.

    “Moreover, in contrast with BIO101, Ang-1-7 is cleaved into several peptides (Ang-1-5, Ang-1-4, and others) susceptible to evoke different biological effects.”

  • The paper relies on this without support.

    BIO101 does not interfere with AT1R like TRV-027.

    “Because BIO101 does not interfere with AT1R like TRV-027, our positive results in COVID-19 perhaps suggest a particular importance of MasR activation in the regulation of respiratory function.28”

  • The paper relies on this without support.

    The improvement in respiratory function with C21 in severe COVID-19 was not confirmed by a subsequent phase 3 study (ATTRACT-3).

    “but this was not confirmed by the results of a subsequent phase 3 study (ATTRACT-3, NCT04880642), communicated through a press release.”

  • The paper relies on this without support.

    During the inclusion period the standard of care evolved with the use of hydroxychloroquine being replaced mostly with remdesivir and the use of corticosteroids.

    “Moreover, during the inclusion period the standard of care evolved as well with the use of hydroxychloroquine being replaced mostly with remdesivir and the use of corticosteroids (particularly dexamethasone).”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The dose of 350 mg bid was selected as the highest dose to be tested in the Phase 2 study based on Phase 1 results showing a good safety and pharmacokinetic profile without effect on blood pressure or other identified adverse drug reactions.

    “The dose of 350 mg bid was selected as the highest dose to be tested in the Phase 2 study based on the results of a Phase 1 study in adult (≥ 18 years) including older (≥ 65 years) healthy volunteers showing a good safety and pharmacokinetic profile without effect on blood pressure [16] or other identified adverse drug reactions [17].”

    From BIO101 in Sarcopenic Seniors at Risk of Mobility Disability: Results of a Double-Blind Randomised Interventional Phase 2b Trial (2025) · cites this paper as [17]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Phytoecdysteroids exert mostly beneficial effects on mammals, with hardly any detrimental results after administration.

    “Phytoecdysteroids have been found to exert mostly beneficial effects on mammals. In fact, hardly any detrimental results have been observed after the administration of these compounds [1,2,3].”

    From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [3]

    The Discussion (page not provided) reports a benefit and a favorable safety profile for BIO101, a 20-hydroxyecdysone treatment, in adults hospitalized with severe COVID-19. The Safety outcomes section also reports treatment-related adverse events, so the paper does not establish the broader claim that phytoecdysteroids generally have mostly beneficial effects and hardly any detrimental results across mammals. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Emerging data indicate that 20-hydroxyecdysone can significantly enhance muscle function in geriatric populations and may reduce the risk of mortality and respiratory failure following COVID-19 infection.

    “Furthermore, emerging data indicate that 20E can significantly enhance muscle function in geriatric populations and may reduce the risk of mortality and respiratory failure following COVID-19 infection [27,28].”

    From How reliable is the labeling of a commercial phytosteroid product? A 12-week randomized double-blind training study (2025) · cites this paper as [27]

    The Discussion (page unavailable) reports a statistically significant reduction in the combined endpoint of death or respiratory failure among adults hospitalized with severe COVID-19. The paper does not report a significant improvement in muscle function in geriatric populations, and it notes that the difference in deaths alone did not reach statistical significance. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Placebo low-flow oxygen count exceeds oxygen-supplementation count

    Minor

    At the time of intervention, Table 1 lists 25 placebo patients receiving low-flow oxygen but only 24 placebo patients receiving supplemental oxygen in total.

  • Primary-outcome text cites the mortality figure

    Minor

    The text directs readers to Fig. 2B for the day-28 death-or-respiratory-failure outcome, but the figure caption identifies panel B as time to death through day 90; panel A covers negative events.

  • Metabolism-disorder event totals do not add up

    Minor

    The treatment groups report 3 and 25 events, which sum to 28 rather than the reported 62. The BIO101 entry also lists fewer events than affected subjects.

    Reported 62 · recomputed 28

  • Grade 3-or-higher adverse-event totals do not add up

    Minor

    The treatment groups report 67 and 88 events, which sum to 155, not the reported total of 160 events.

    Reported 160 · recomputed 155

  • Key secondary endpoint has two p-values

    Minor

    The text reports p = 0.0568 for the key secondary endpoint, whereas Table 2A reports p = 0.0586 for the same comparison.

5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Song, 2019, Protective effect of 20-hydroxyecdysterone against lipopolysaccharides-induced acute lung injury in mice, J Pharm Drug Res, 2, 109

Cited by

Sorted by citations

Related

Authors
Lobo, S. M., Plantefève, G., Nair, G., Joaquim Cavalcante, A., Franzin de Moraes, N., Nunes, E., Barnum, O., Berdun Stadnik, C. M., Lima, M. P., Lins, M., Hajjar, L. A., Lipinski, C., Islam, S., Ramos, F., Simon, T., Martinot, J.-B., Guimard, T., Desclaux, A., Lioger, B., Neuenschwander, F. C., DeSouza Paolino, B., Amin, A., Acosta, S. A., Dilling, D. F., Cartagena, E., Snyder, B., Devaud, E., Barreto Berselli Marinho, A. K., Tanni, S., Milhomem Beato, P. M., De Wit, S., Selvan, V., Gray, J., Fernandez, R., Pourcher, V., Maddox, L., Kay, R., Azbekyan, A., Chabane, M., Tourette, C., Esmeraldino, L. E., Dilda, P. J., Lafont, R., Mariani, J., Camelo, S., Rabut, S., Agus, S., Veillet, S., Dioh, W., van Maanen, R., & Morelot-Panzini, C.
Affiliations
  • Faculdade de Medicina de São José do Rio Preto (BR)
  • Corewell Health William Beaumont University Hospital (US)
  • Hospital e Maternidade Celso Pierro (BR)
  • AZ Sint-Maarten (BE)
  • Augusta University (US)
  • Hospital São Lucas da PUCRS (BR)
  • Centre Hospitalier Départemental Vendée (FR)
  • Centre Hospitalier Universitaire de Bordeaux (FR)
  • University of California, Irvine (US)
  • Loyola University Medical Center (US)
  • San Juan Bautista School of Medicine (PR)
  • Hôpital NOVO (FR)
  • Universidade Estadual Paulista (Unesp) (BR)
  • Texas Tech University Health Sciences Center (US)
  • United Health Services (US)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • WellSpan York Hospital (US)
  • Sorbonne Université (FR)
  • Centre National de la Recherche Scientifique (FR)
ORCID
Venue
eClinicalMedicine
Publisher
Elsevier BV
Published
2024-02
Volume
68
Pages
102383
ISSN
2589-5370 (ISSN-L)
DOI
10.1016/j.eclinm.2023.102383
PMC
PMC10965409
OpenAlex
W4390572175
Semantic Scholar
d262e3fb653c1868a8b537efde4b21daffe421b1
Cited by
27
References
33
Citations by year
2026: 8 · 2025: 11 · 2024: 8
FWCI
9.28
Type
journal article
Language
en
Open access
Licence
Locations
  • EClinicalMedicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
  • Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
  • Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
20-hydroxyecdysone, severe COVID-19, renin-angiotensin system, respiratory failure, mortality, hospital discharge, ACE2, SARS-CoV-2, hospitalized adults, treatment-emergent adverse events, mechanical ventilation, extracorporeal membrane oxygenation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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