Adaptive Design, Phase 2-3, Randomized, Double-blind, Multicenter Study, Evaluating Safety, Efficacy, PK-PD of BIO101 in Prevention of Respiratory Deterioration in Hospitalized Patients With COVID-19 Pneumonia (Severe)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- Biophytis
- 入组人数
- 238
- 试验地点
- 33
- 主要终点
- For part-2 sample size interim analysis: Proportion of subjects with all cause mortality or with respiratory failure.
研究概览
简要总结
The COVA clinical study is a global multicentric, double-blind, placebo-controlled, group sequential and adaptive 2 parts phase 2-3 study targeting in participants with SARS-CoV-2 pneumonia. Part 1 is a Phase 2 exploratory Proof of Concept (PoC) study to provide preliminary data on the activity, safety and tolerability of BIO101 in the target population. Part 2 is a phase 3 pivotal randomized study to provide further evidence of safety and efficacy of BIO101 after 28 days of double-blind dosing. BIO101 is the investigational new drug that activates the Mas receptor (MasR) through the protective arm of the Renin Angiotensin System (RAS).
详细描述
Biophytis is developing BIO101, an investigational new drug, an oral preparation of immediate-release 20-hydroxyecdysone (20E) at ≥ 97% purity. BIO101 activates MasR on the protective arm of the Renin Angiotensin System (RAS). The engagement of MasR by BIO101 is responsible for a number of preclinical beneficial activities in normal and pathological contexts.
The COVA clinical study is a global, multicentric, double-blind, placebo-controlled, group sequential and adaptive 2 parts phase 2-3 study in participants with SARS-CoV-2 pneumonia. Part 1 is a Phase 2 exploratory Proof of Concept (PoC) study to provide preliminary data on the activity, safety and tolerability of BIO101 in the target population. Part 2 is a phase 3 pivotal randomized study to provide further evidence of safety and efficacy of BIO101 after 28 days of dosing.
The trial will use an adaptive design based on pre-specified criteria, using an independent external Data Monitoring Committee (DMC) to monitor safety, efficacy, and review data at appropriate intervals to allow the initiation of the confirmatory part of the study.
The general objectives of the study are:
- The purpose of Part 1 is to obtain preliminary indication of activity of BIO101, in preventing respiratory deterioration in the target population (50 participants, age ≥ 55 years) and provide preliminary data on the safety and tolerability of BIO101 in the target population
- The purpose of Part 2 is to re-assess the sample size that is needed for the confirmatory part of the study and to provide confirmation on the benefit of BIO101 and safety in the larger target population (up to 310 participants)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 45 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: 45 and older (in France: 55 and older)
- •A confirmed diagnosis of COVID-19 infection, within the last 28 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 days
- •a. Participants can be included even if treated with: oxygen supplementation, High-flow oxygen (HFO2), bilevel positive airway pressure (BiPAP) and continuous positive airway pressure (CPAP)
- •With evidence of pneumonia based on all of the following:
- •Clinical findings on a physical examination
- •Respiratory symptoms developed within the past 14 days
- •With evidence of respiratory decompensation that started not more than 7 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 minute
- •Arterial 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 criterion
- •Without a significant deterioration in liver function tests:
- •ALT and AST ≤ 5x upper limit of normal (ULN)
- •Gamma-glutamyl transferase (GGT) ≤ 5x ULN
- •Total bilirubin ≤ 5×ULN
- •Willing to participate and able to sign an informed consent form (ICF)
- •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
- •Have a negative urine pregnancy test at screening
- •Be 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 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.
- •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 investigational product;
- •For France only: Being affiliated with a European Social Security.
排除标准
- •Not needing or not willing to remain in a healthcare facility during the entire study medication (i.e. while receiving study medication)
- •Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions
- •Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO)
- •Participant within 7 days of participating in other therapeutic clinical trial with angiotensin-converting-enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or recombinant ACE-2
- •Participant not able to take medications by mouth (as capsules or as a powder, mixed in water).
- •Disallowed concomitant medication:
- •a. 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
- •Non-affiliation to compulsory French social security scheme (beneficiary or right-holder)
- •Being under tutelage or legal guardianship
研究组 & 干预措施
Placebo
Placebo
干预措施: Placebo (Drug)
BIO101
BIO101 350 mg twice daily (BID)
干预措施: BIO101 (Drug)
结局指标
主要结局
For part-2 sample size interim analysis: Proportion of subjects with all cause mortality or with respiratory failure.
时间窗: up to 28 days
For sample size re-assessment for part 2, time frame - up to 28 days: • Proportion of participants with negative events, of either of the following: * All-cause mortality * Respiratory failure, defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage) Requiring ECMO
For the final analysis: Proportion of subjects with all cause mortality or respiratory failure.
时间窗: up to 28 days
• Proportion of participants with of subjects with negative events, of either of the following. * All-cause mortality * Respiratory failure, defined as any of the following: Mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage) Requiring ECMO
End-of-Part 1 interim analysis: Proportion of subjects with all cause mortality or with respiratory failure.
时间窗: up to 28 days
For interim analysis intended to obtain indication of activity of BIO101. Primary endpoint: • Proportion of subjects with negative events, of either of the following: * All-cause mortality * Respiratory failure, defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage) Requiring ECMO
Percentage of Participants Experiencing Negative Events
时间窗: Up to 28 days
Negative events were defined as: all-cause mortality, respiratory failure requiring mechanical ventilation (including cases that were not intubated due to resource restrictions and triage), respiratory failure requiring extracorporeal membrane oxygenation (ECMO), and respiratory failure requiring high-flow oxygen (HFO2). Only the first occurrence of any negative event up to day 28 was considered for the analysis.
次要结局
- Interim analysis; indication of activity of BIO101: Inflammatory markers(28 days)
- Key secondary endpoint for final analysis: Proportion of participants with positive events(Up to 28 days)
- Additional secondary endpoint: Proportion of participants with events of all-cause mortality(Up to 28 days)
- Additional secondary endpoint: time to event: positive events(Up to 28 days)
- Interim analysis; indication of activity of BIO101: Renin Angiotensin System biomarkers(28 days)
- Additional secondary endpoint for final analysis: Population Pharmacokinetics study (pop-PK)(1day)
- Additional secondary endpoints for final analysis: Respiratory function(28 days)
- Additional secondary endpoint for final analysis: The National Early Warning Score 2 (NewS2):(28 days)
- Additional secondary endpoint : Population Pharmacokinetics study (pop-PK)(1 day)
- Interim analysis; indication of activity of BIO101: Oxygen saturation by pulse oximetry (SpO2) SpO2 / Fraction of inspired oxygen (FiO2) ratio(28 days)
- Additional secondary endpoints for final analysis:proportion of patients who experienced negative events(28 days)
- Additional secondary endpoint: Population Pharmacokinetics study (pop-PK)(1 day)
- Additional secondary endpoint: time to event: negative events(Up to 28 days)
- Number of Participants Experiencing Positive Events(Up to 28 days)
- Change From Baseline in Saturation by Pulse Oximetry (SpO2)/Fraction of Inspired Oxygen (FiO2) Ratio(Day 3, Day 7, Day 14, and Day 28)
- Change From Baseline in Oxygen Saturation in Arterial Blood as Measured by SpO2(Day 3, Day 7, Day 14, and Day 28)
- Number of Participants Experiencing All-cause Mortality(Up to 90 days)
- Time to Reach a Negative Event(Up to 28 days)
- Time to Reach a Positive Event(Up to 28 days)
- Change From Baseline in National Early Warning Score 2 (NEWS2)(Day 3, Day 7, Day 14, and Day 28)
- Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)(Up to 90 days)
- Number of Participants Experiencing TEAEs of Special Interest (EOI)(Up to 90 days)