Testing the efficacy and safety of BIO101, for the prevention of respiratory deterioration, in patients with COVID-19 pneumonia (COVA study): ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2021-01-11

AUTHORS

W. Dioh, M. Chabane, C. Tourette, A. Azbekyan, C. Morelot-Panzini, L. A. Hajjar, M. Lins, G. B. Nair, T. Whitehouse, J. Mariani, M. Latil, S. Camelo, R. Lafont, P. J. Dilda, S. Veillet, S. Agus

ABSTRACT

ObjectivesAs of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage.The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia.Trial designRandomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts.Part 1:Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target populationPart 2:Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population.The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive – to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial.ParticipantsInclusion criteria Age: 45 and aboveA confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used.Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 daysWith evidence of pneumonia based on all of the following: Clinical findings on a physical examinationRespiratory symptoms developed within the past 7 daysWith evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: Tachypnea: ≥25 breaths per minuteArterial oxygen saturation ≤92%A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterionWithout a significant deterioration in liver function tests: ALT and AST ≤ 5x upper limit of normal (ULN)Gamma-glutamyl transferase (GGT) ≤ 5x ULNTotal bilirubin ≤ 5×ULNWilling to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participantFemale participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR Have a negative urine pregnancy test at screeningBe willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose.Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product.(Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy).Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention.Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product.For France only: Being affiliated with a European Social Security.Exclusion criteria Not needing or not willing to remain in a healthcare facility during the studyMoribund condition (death likely in days) or not expected to survive for >7 days – due to other and non-COVID-19 related conditionsParticipant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.).Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water).Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents).Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101.Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula).In France only: Non-affiliation to compulsory French social security scheme (beneficiary or right-holder).Being under tutelage or legal guardianship.Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients’ participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days.Intervention and comparatorTwo treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., ‘negative’ or ‘positive’ event). Participants who are officially discharged from hospital care will no longer receive study medication.Main outcomesPrimary study endpoint:The proportion of participants with ‘negative’ events up to 28 days.‘Negative’ events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage).Requiring extracorporeal membrane oxygenation (ECMO).Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min.Only if the primary endpoint is significant at the primary final analysis the followingKey secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28Proportion of participants with ‘positive’ events at Day 28.Proportion of participants with events of all-cause mortality at Day 28A ‘positive’ event is defined as the official discharge from hospital care by the department due to improvement in participant condition.Secondary and exploratory endpoints:In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected.RandomizationRandomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above).In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not).Blinding (masking)Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacy data, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power.Numbers to be randomised (sample size)Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients).Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1).Trial StatusThe current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021.Trial registrationThe trial was registered before trial start in trial registries: EudraCT, No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728, registered July 15, 2020.Full protocolThe full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. More... »

PAGES

42

Journal

TITLE

Trials

ISSUE

1

VOLUME

22

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13063-020-04998-5

DOI

http://dx.doi.org/10.1186/s13063-020-04998-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1134472257

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/33430924


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    "description": "ObjectivesAs of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage.The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia.Trial designRandomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts.Part 1:Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target populationPart 2:Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population.The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive \u2013 to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial.ParticipantsInclusion criteria\nAge: 45 and aboveA confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used.Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration \u22653 daysWith evidence of pneumonia based on all of the following:\nClinical findings on a physical examinationRespiratory symptoms developed within the past 7 daysWith evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff:\nTachypnea: \u226525 breaths per minuteArterial oxygen saturation \u226492%A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterionWithout a significant deterioration in liver function tests:\nALT and AST \u2264 5x upper limit of normal (ULN)Gamma-glutamyl transferase (GGT) \u2264 5x ULNTotal bilirubin \u2264 5\u00d7ULNWilling to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participantFemale participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR\nHave a negative urine pregnancy test at screeningBe willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose.Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product.(Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy).Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention.Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product.For France only: Being affiliated with a European Social Security.Exclusion criteria\nNot needing or not willing to remain in a healthcare facility during the studyMoribund condition (death likely in days) or not expected to survive for >7 days \u2013 due to other and non-COVID-19 related conditionsParticipant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of \u226516 L/min.).Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water).Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents).Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101.Renal disease requiring dialysis, or known renal insufficiency (eGFR\u226430 mL/min/1.73 m2, based on Cockcroft & Gault formula).In France only:\nNon-affiliation to compulsory French social security scheme (beneficiary or right-holder).Being under tutelage or legal guardianship.Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients\u2019 participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (\u00b1 2) and 60 (\u00b1 4) days.Intervention and comparatorTwo treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., \u2018negative\u2019 or \u2018positive\u2019 event). Participants who are officially discharged from hospital care will no longer receive study medication.Main outcomesPrimary study endpoint:The proportion of participants with \u2018negative\u2019 events up to 28 days.\u2018Negative\u2019 events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following:\nRequiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage).Requiring extracorporeal membrane oxygenation (ECMO).Requiring high-flow oxygen defined as delivery of oxygen at a flow of \u226516 L/min.Only if the primary endpoint is significant at the primary final analysis the followingKey secondary endpoints will be tested in that order:\nProportion of participants with events of respiratory failure at Day 28Proportion of participants with \u2018positive\u2019 events at Day 28.Proportion of participants with events of all-cause mortality at Day 28A \u2018positive\u2019 event is defined as the official discharge from hospital care by the department due to improvement in participant condition.Secondary and exploratory endpoints:In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected.RandomizationRandomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio.\nIn part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above).In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not).Blinding (masking)Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacy data, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power.Numbers to be randomised (sample size)Number of participants randomized: up to 465, in total\nPart 1: 50 (to obtain the proof of concept in COVID-19 patients).Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1).Trial StatusThe current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021.Trial registrationThe trial was registered before trial start in trial registries: EudraCT, No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728, registered July 15, 2020.Full protocolThe full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.", 
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32 schema:description ObjectivesAs of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage.The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia.Trial designRandomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts.Part 1:Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target populationPart 2:Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population.The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive – to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial.ParticipantsInclusion criteria Age: 45 and aboveA confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used.Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 daysWith evidence of pneumonia based on all of the following: Clinical findings on a physical examinationRespiratory symptoms developed within the past 7 daysWith evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: Tachypnea: ≥25 breaths per minuteArterial oxygen saturation ≤92%A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterionWithout a significant deterioration in liver function tests: ALT and AST ≤ 5x upper limit of normal (ULN)Gamma-glutamyl transferase (GGT) ≤ 5x ULNTotal bilirubin ≤ 5×ULNWilling to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participantFemale participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR Have a negative urine pregnancy test at screeningBe willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose.Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product.(Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy).Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention.Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product.For France only: Being affiliated with a European Social Security.Exclusion criteria Not needing or not willing to remain in a healthcare facility during the studyMoribund condition (death likely in days) or not expected to survive for >7 days – due to other and non-COVID-19 related conditionsParticipant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.).Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water).Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents).Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101.Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula).In France only: Non-affiliation to compulsory French social security scheme (beneficiary or right-holder).Being under tutelage or legal guardianship.Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients’ participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days.Intervention and comparatorTwo treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., ‘negative’ or ‘positive’ event). Participants who are officially discharged from hospital care will no longer receive study medication.Main outcomesPrimary study endpoint:The proportion of participants with ‘negative’ events up to 28 days.‘Negative’ events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage).Requiring extracorporeal membrane oxygenation (ECMO).Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min.Only if the primary endpoint is significant at the primary final analysis the followingKey secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28Proportion of participants with ‘positive’ events at Day 28.Proportion of participants with events of all-cause mortality at Day 28A ‘positive’ event is defined as the official discharge from hospital care by the department due to improvement in participant condition.Secondary and exploratory endpoints:In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected.RandomizationRandomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above).In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not).Blinding (masking)Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacy data, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power.Numbers to be randomised (sample size)Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients).Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1).Trial StatusThe current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021.Trial registrationThe trial was registered before trial start in trial registries: EudraCT, No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728, registered July 15, 2020.Full protocolThe full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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112 conditions
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115 consent form
116 consumption
117 contraceptive methods
118 control
119 coronavirus disease 2019
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126 days
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132 design
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135 diabetes
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141 dissemination
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157 endotracheal tube
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159 entry
160 enzyme 2
161 events
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163 excipients
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167 facilities
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171 files
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175 first one
176 flow
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180 function
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184 gender
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191 healthcare facilities
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208 infection
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213 interaction
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216 intervention
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219 investigational product
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228 male participants
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232 medical interventions
233 medications
234 membrane oxygenation
235 method
236 min
237 moderate symptoms
238 months
239 mortality
240 mouth
241 multiorgan dysfunction
242 myocarditis
243 negative urine pregnancy test
244 new therapeutic options
245 new treatment options
246 note
247 number
248 obesity
249 objective
250 observations
251 older people
252 one
253 options
254 order
255 outcomes
256 oxygen
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258 oxygenation
259 part
260 participant condition
261 participants
262 participation
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264 patients
265 people
266 pericarditis
267 period
268 pharmaceutical grade
269 phone calls
270 picture
271 placebo
272 placebo b.
273 placebo comparator arm
274 players
275 pneumonia
276 population
277 positive airway pressure
278 power
279 pregnancy test
280 preliminary indication
281 presence
282 pressure
283 prevention
284 primary endpoint
285 principles
286 process
287 products
288 properties
289 proportion
290 proportion of participants
291 protein
292 protocol
293 protocol version
294 purpose
295 purpose of reproduction
296 randomization
297 ratio
298 receptor activator
299 receptors
300 recruitment
301 registry
302 renal insufficiency
303 renin-angiotensin system
304 representatives
305 reproduction
306 respiratory decompensation
307 respiratory deterioration
308 respiratory distress syndrome
309 respiratory failure
310 respiratory function
311 risk
312 run
313 safety
314 sample size
315 samples
316 saturation
317 scheme
318 screening
319 second interim analysis
320 secondary endpoints
321 seconds
322 security
323 security scheme
324 severe form
325 severe pneumonia
326 severe stages
327 shock
328 significant deterioration
329 size
330 social security
331 social security schemes
332 special note
333 specimen
334 sperm
335 spike protein
336 staff
337 stage
338 start
339 start of recruitment
340 statistical power
341 structured summary
342 study
343 study entry
344 study medication
345 study protocol
346 study team
347 summary
348 survival
349 suspicion
350 symptoms
351 syndrome
352 system
353 tachypnea
354 target population
355 team
356 test
357 therapeutic options
358 therapeutic units
359 tolerability
360 toll
361 transferase
362 treatment arms
363 treatment options
364 treatment period
365 trials
366 tube
367 tutelage
368 units
369 upper limit
370 urine pregnancy test
371 use
372 vaga
373 variety
374 ventilation
375 version
376 visits
377 websites
378 whole study
379 whole treatment period
380 years
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