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Inflammaging

Id Subject Object Predicate Lexical cue
T1 0-217 Sentence denotes Testing the efficacy and safety of BIO101, for the prevention of respiratory deterioration, in patients with COVID-19 pneumonia (COVA study): a structured summary of a study protocol for a randomised controlled trial.
T2 218-229 Sentence denotes OBJECTIVES:
T3 230-413 Sentence denotes As 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.
T4 414-534 Sentence denotes Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention.
T5 535-663 Sentence denotes However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality.
T6 664-956 Sentence denotes 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.
T7 957-1036 Sentence denotes The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2.
T8 1037-1178 Sentence denotes Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS).
T9 1179-1370 Sentence denotes 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.
T10 1371-1569 Sentence denotes 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.
T11 1570-1690 Sentence denotes Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties.
T12 1691-1934 Sentence denotes 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.
T13 1935-2118 Sentence denotes 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.
T14 2119-2132 Sentence denotes TRIAL DESIGN:
T15 2133-2258 Sentence denotes Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts.
T16 2259-2266 Sentence denotes Part 1:
T17 2267-2448 Sentence denotes Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2:
T18 2449-2602 Sentence denotes 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.
T19 2603-2751 Sentence denotes The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation.
T20 2752-2909 Sentence denotes 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.
T21 2910-2923 Sentence denotes PARTICIPANTS:
T22 2924-2945 Sentence denotes Inclusion criteria 1.
T23 2946-2950 Sentence denotes Age:
T24 2951-2966 Sentence denotes 45 and above 2.
T25 2967-3179 Sentence denotes A 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.
T26 3180-3182 Sentence denotes 3.
T27 3183-3329 Sentence denotes Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4.
T28 3330-3390 Sentence denotes With evidence of pneumonia based on all of the following: a.
T29 3391-3437 Sentence denotes Clinical findings on a physical examination b.
T30 3438-3494 Sentence denotes Respiratory symptoms developed within the past 7 days 5.
T31 3495-3706 Sentence denotes With 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: a.
T32 3707-3743 Sentence denotes Tachypnea: ≥25 breaths per minute b.
T33 3744-3778 Sentence denotes Arterial oxygen saturation ≤92% c.
T34 3779-3937 Sentence denotes 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 criterion 6.
T35 3938-4001 Sentence denotes Without a significant deterioration in liver function tests: a.
T36 4002-4049 Sentence denotes ALT and AST ≤ 5x upper limit of normal (ULN) b.
T37 4050-4094 Sentence denotes Gamma-glutamyl transferase (GGT) ≤ 5x ULN c.
T38 4095-4121 Sentence denotes Total bilirubin ≤ 5×ULN 7.
T39 4122-4193 Sentence denotes Willing to participate and able to sign an informed consent form (ICF).
T40 4194-4311 Sentence denotes Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8.
T41 4312-4489 Sentence denotes Female 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 a.
T42 4490-4542 Sentence denotes Have a negative urine pregnancy test at screening b.
T43 4543-4663 Sentence denotes Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose.
T44 4664-4666 Sentence denotes 9.
T45 4667-5205 Sentence denotes 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).
T46 5206-5209 Sentence denotes 10.
T47 5210-5335 Sentence denotes Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention.
T48 5336-5339 Sentence denotes 11.
T49 5340-5522 Sentence denotes 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.
T50 5523-5526 Sentence denotes 12.
T51 5527-5543 Sentence denotes For France only:
T52 5544-5593 Sentence denotes Being affiliated with a European Social Security.
T53 5594-5615 Sentence denotes Exclusion criteria 1.
T54 5616-5697 Sentence denotes Not needing or not willing to remain in a healthcare facility during the study 2.
T55 5698-5832 Sentence denotes Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3.
T56 5833-6018 Sentence denotes Participant 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.).
T57 6019-6021 Sentence denotes 4.
T58 6022-6120 Sentence denotes Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water).
T59 6121-6123 Sentence denotes 5.
T60 6124-6158 Sentence denotes Disallowed concomitant medication:
T61 6159-6351 Sentence denotes 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).
T62 6352-6354 Sentence denotes 6.
T63 6355-6455 Sentence denotes Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101.
T64 6456-6458 Sentence denotes 7.
T65 6459-6583 Sentence denotes Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula).
T66 6584-6586 Sentence denotes 8.
T67 6587-6605 Sentence denotes In France only: a.
T68 6606-6699 Sentence denotes Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b.
T69 6700-6743 Sentence denotes Being under tutelage or legal guardianship.
T70 6744-6857 Sentence denotes Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil.
T71 6858-6921 Sentence denotes Maximum patients' participation in the study will last 28 days.
T72 6922-7059 Sentence denotes Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days.
T73 7060-7088 Sentence denotes INTERVENTION AND COMPARATOR:
T74 7089-7256 Sentence denotes Two 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.
T75 7257-7336 Sentence denotes Administration of daily dose is the same throughout the whole treatment period.
T76 7337-7500 Sentence denotes 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).
T77 7501-7603 Sentence denotes Participants who are officially discharged from hospital care will no longer receive study medication.
T78 7604-7618 Sentence denotes MAIN OUTCOMES:
T79 7619-7642 Sentence denotes Primary study endpoint:
T80 7643-7795 Sentence denotes The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality.
T81 7796-7893 Sentence denotes For the purpose of this study, respiratory deterioration will be defined as any of the following:
T82 7894-8012 Sentence denotes Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage).
T83 8013-8066 Sentence denotes Requiring extracorporeal membrane oxygenation (ECMO).
T84 8067-8147 Sentence denotes Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min.
T85 8148-8289 Sentence denotes Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order:
T86 8290-8422 Sentence denotes Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28.
T87 8423-8632 Sentence denotes Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition.
T88 8633-8669 Sentence denotes Secondary and exploratory endpoints:
T89 8670-8880 Sentence denotes 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.
T90 8881-8895 Sentence denotes RANDOMIZATION:
T91 8896-8995 Sentence denotes Randomization is performed using an IBM clinical development IWRS system during the baseline visit.
T92 8996-9085 Sentence denotes Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio.
T93 9086-9210 Sentence denotes In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above).
T94 9211-9545 Sentence denotes 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).
T95 9546-9565 Sentence denotes BLINDING (MASKING):
T96 9566-9666 Sentence denotes Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment.
T97 9667-9796 Sentence denotes All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process.
T98 9797-9876 Sentence denotes An independent data-monitoring committee (DMC) will conduct 2 interim analyses.
T99 9877-9965 Sentence denotes A first one based on the data from part 1 and a second from the data from parts 1 and 2.
T100 9966-10137 Sentence denotes 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.
T101 10138-10281 Sentence denotes The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power.
T102 10282-10383 Sentence denotes Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1:
T103 10384-10441 Sentence denotes 50 (to obtain the proof of concept in COVID-19 patients).
T104 10442-10449 Sentence denotes Part 2:
T105 10450-10579 Sentence denotes 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1).
T106 10580-10593 Sentence denotes TRIAL STATUS:
T107 10594-10654 Sentence denotes The current protocol Version is V 10.0, dated on 24.09.2020.
T108 10655-10779 Sentence denotes The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021.
T109 10780-10799 Sentence denotes TRIAL REGISTRATION:
T110 10800-10864 Sentence denotes The trial was registered before trial start in trial registries:
T111 10865-10878 Sentence denotes EudraCT , No.
T112 10879-10994 Sentence denotes 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 2020.
T113 10995-11009 Sentence denotes FULL PROTOCOL:
T114 11010-11118 Sentence denotes The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).
T115 11119-11299 Sentence denotes 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.
T1 0-217 Sentence denotes Testing the efficacy and safety of BIO101, for the prevention of respiratory deterioration, in patients with COVID-19 pneumonia (COVA study): a structured summary of a study protocol for a randomised controlled trial.
T2 218-229 Sentence denotes OBJECTIVES:
T3 230-413 Sentence denotes As 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.
T4 414-534 Sentence denotes Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention.
T5 535-663 Sentence denotes However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality.
T6 664-956 Sentence denotes 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.
T7 957-1036 Sentence denotes The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2.
T8 1037-1178 Sentence denotes Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS).
T9 1179-1370 Sentence denotes 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.
T10 1371-1569 Sentence denotes 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.
T11 1570-1690 Sentence denotes Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties.
T12 1691-1934 Sentence denotes 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.
T13 1935-2118 Sentence denotes 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.
T14 2119-2132 Sentence denotes TRIAL DESIGN:
T15 2133-2258 Sentence denotes Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts.
T16 2259-2266 Sentence denotes Part 1:
T17 2267-2448 Sentence denotes Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2:
T18 2449-2602 Sentence denotes 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.
T19 2603-2751 Sentence denotes The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation.
T20 2752-2909 Sentence denotes 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.
T21 2910-2923 Sentence denotes PARTICIPANTS:
T22 2924-2945 Sentence denotes Inclusion criteria 1.
T23 2946-2950 Sentence denotes Age:
T24 2951-2966 Sentence denotes 45 and above 2.
T25 2967-3179 Sentence denotes A 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.
T26 3180-3182 Sentence denotes 3.
T27 3183-3329 Sentence denotes Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4.
T28 3330-3390 Sentence denotes With evidence of pneumonia based on all of the following: a.
T29 3391-3437 Sentence denotes Clinical findings on a physical examination b.
T30 3438-3494 Sentence denotes Respiratory symptoms developed within the past 7 days 5.
T31 3495-3706 Sentence denotes With 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: a.
T32 3707-3743 Sentence denotes Tachypnea: ≥25 breaths per minute b.
T33 3744-3778 Sentence denotes Arterial oxygen saturation ≤92% c.
T34 3779-3937 Sentence denotes 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 criterion 6.
T35 3938-4001 Sentence denotes Without a significant deterioration in liver function tests: a.
T36 4002-4049 Sentence denotes ALT and AST ≤ 5x upper limit of normal (ULN) b.
T37 4050-4094 Sentence denotes Gamma-glutamyl transferase (GGT) ≤ 5x ULN c.
T38 4095-4121 Sentence denotes Total bilirubin ≤ 5×ULN 7.
T39 4122-4193 Sentence denotes Willing to participate and able to sign an informed consent form (ICF).
T40 4194-4311 Sentence denotes Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8.
T41 4312-4489 Sentence denotes Female 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 a.
T42 4490-4542 Sentence denotes Have a negative urine pregnancy test at screening b.
T43 4543-4663 Sentence denotes Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose.
T44 4664-4666 Sentence denotes 9.
T45 4667-5205 Sentence denotes 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).
T46 5206-5209 Sentence denotes 10.
T47 5210-5335 Sentence denotes Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention.
T48 5336-5339 Sentence denotes 11.
T49 5340-5522 Sentence denotes 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.
T50 5523-5526 Sentence denotes 12.
T51 5527-5543 Sentence denotes For France only:
T52 5544-5593 Sentence denotes Being affiliated with a European Social Security.
T53 5594-5615 Sentence denotes Exclusion criteria 1.
T54 5616-5697 Sentence denotes Not needing or not willing to remain in a healthcare facility during the study 2.
T55 5698-5832 Sentence denotes Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3.
T56 5833-6018 Sentence denotes Participant 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.).
T57 6019-6021 Sentence denotes 4.
T58 6022-6120 Sentence denotes Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water).
T59 6121-6123 Sentence denotes 5.
T60 6124-6158 Sentence denotes Disallowed concomitant medication:
T61 6159-6351 Sentence denotes 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).
T62 6352-6354 Sentence denotes 6.
T63 6355-6455 Sentence denotes Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101.
T64 6456-6458 Sentence denotes 7.
T65 6459-6583 Sentence denotes Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula).
T66 6584-6586 Sentence denotes 8.
T67 6587-6605 Sentence denotes In France only: a.
T68 6606-6699 Sentence denotes Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b.
T69 6700-6743 Sentence denotes Being under tutelage or legal guardianship.
T70 6744-6857 Sentence denotes Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil.
T71 6858-6921 Sentence denotes Maximum patients' participation in the study will last 28 days.
T72 6922-7059 Sentence denotes Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days.
T73 7060-7088 Sentence denotes INTERVENTION AND COMPARATOR:
T74 7089-7256 Sentence denotes Two 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.
T75 7257-7336 Sentence denotes Administration of daily dose is the same throughout the whole treatment period.
T76 7337-7500 Sentence denotes 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).
T77 7501-7603 Sentence denotes Participants who are officially discharged from hospital care will no longer receive study medication.
T78 7604-7618 Sentence denotes MAIN OUTCOMES:
T79 7619-7642 Sentence denotes Primary study endpoint:
T80 7643-7795 Sentence denotes The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality.
T81 7796-7893 Sentence denotes For the purpose of this study, respiratory deterioration will be defined as any of the following:
T82 7894-8012 Sentence denotes Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage).
T83 8013-8066 Sentence denotes Requiring extracorporeal membrane oxygenation (ECMO).
T84 8067-8147 Sentence denotes Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min.
T85 8148-8289 Sentence denotes Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order:
T86 8290-8422 Sentence denotes Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28.
T87 8423-8632 Sentence denotes Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition.
T88 8633-8669 Sentence denotes Secondary and exploratory endpoints:
T89 8670-8880 Sentence denotes 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.
T90 8881-8895 Sentence denotes RANDOMIZATION:
T91 8896-8995 Sentence denotes Randomization is performed using an IBM clinical development IWRS system during the baseline visit.
T92 8996-9085 Sentence denotes Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio.
T93 9086-9210 Sentence denotes In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above).
T94 9211-9545 Sentence denotes 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).
T95 9546-9565 Sentence denotes BLINDING (MASKING):
T96 9566-9666 Sentence denotes Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment.
T97 9667-9796 Sentence denotes All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process.
T98 9797-9876 Sentence denotes An independent data-monitoring committee (DMC) will conduct 2 interim analyses.
T99 9877-9965 Sentence denotes A first one based on the data from part 1 and a second from the data from parts 1 and 2.
T100 9966-10137 Sentence denotes 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.
T101 10138-10281 Sentence denotes The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power.
T102 10282-10383 Sentence denotes Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1:
T103 10384-10441 Sentence denotes 50 (to obtain the proof of concept in COVID-19 patients).
T104 10442-10449 Sentence denotes Part 2:
T105 10450-10579 Sentence denotes 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1).
T106 10580-10593 Sentence denotes TRIAL STATUS:
T107 10594-10654 Sentence denotes The current protocol Version is V 10.0, dated on 24.09.2020.
T108 10655-10779 Sentence denotes The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021.
T109 10780-10799 Sentence denotes TRIAL REGISTRATION:
T110 10800-10864 Sentence denotes The trial was registered before trial start in trial registries:
T111 10865-10878 Sentence denotes EudraCT , No.
T112 10879-10994 Sentence denotes 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 2020.
T113 10995-11009 Sentence denotes FULL PROTOCOL:
T114 11010-11118 Sentence denotes The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).
T115 11119-11299 Sentence denotes 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.