Covid-19, SARS-CoV2
Conditions
Brief summary
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).
Detailed description
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)
Interventions
DRUGBIO101
BIO101 capsules
DRUGPlacebo
placebo capsules
Sponsors
Biophytis
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age: 45 and older (in France: 55 and older) 2. 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. 3. 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) 4. With evidence of pneumonia based on all of the following: 1. Clinical findings on a physical examination 2. Respiratory symptoms developed within the past 14 days 5. 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: 1. Tachypnea: ≥25 breaths per minute 2. Arterial oxygen saturation ≤92% 3. 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. Without a significant deterioration in liver function tests: 1. ALT and AST ≤ 5x upper limit of normal (ULN) 2. Gamma-glutamyl transferase (GGT) ≤ 5x ULN 3. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF) 8. 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 1. Have a negative urine pregnancy test at screening 2. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. 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. 10. 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; 11. For France only: Being affiliated with a European Social Security.
Exclusion criteria
1. Not needing or not willing to remain in a healthcare facility during the entire study medication (i.e. while receiving study medication) 2. Moribund condition (death likely in days) or not expected to survive for \>7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO) 4. 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 5. Participant not able to take medications by mouth (as capsules or as a powder, mixed in water). 6. 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) 7. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101 8. In France: * Non-affiliation to compulsory French social security scheme (beneficiary or right-holder) * Being under tutelage or legal guardianship
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Negative Events | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Positive Events | Up to 28 days | Positive events were defined as participants being officially discharged from hospital care by the department due to improvement in participant condition (self-discharge by participant was not considered a positive event). |
| Change From Baseline in Saturation by Pulse Oximetry (SpO2)/Fraction of Inspired Oxygen (FiO2) Ratio | Day 3, Day 7, Day 14, and Day 28 | SpO2/fraction of inspired oxygen (FiO2). Oxygen saturation in arterial blood, measured by pulse-oximetry (SpO2). Peripheral arterial oxygen saturation (SpO2) estimates the amount of oxygen in the blood, expressing the percentage of oxygenated hemoglobin compared to the total amount of hemoglobin It will be measured by pulse oximetry, an indirect and non-invasive method. The FiO2 and the oxygen delivery system (e.g., simple facial mask; partial rebreather mask; nasal cannula; C-PAP machine) are to be recorded. If FiO2 cannot be read directly from the device, the volume (in liters) and % of oxygen the system delivers (e.g., 100%) should be recorded instead. Ratio between SpO2 and FiO2 is calculated |
| Change From Baseline in Oxygen Saturation in Arterial Blood as Measured by SpO2 | Day 3, Day 7, Day 14, and Day 28 | Oxygen saturation in arterial blood, measured by pulse-oximetry (SpO2). Peripheral arterial oxygen saturation (SpO2) estimates the amount of oxygen in the blood, expressing the percentage of oxygenated hemoglobin compared to the total amount of hemoglobin It will be measured by pulse oximetry, an indirect and non-invasive method. |
| Number of Participants Experiencing All-cause Mortality | Up to 90 days | All-cause mortality refers to the overall death rate in a population, irrespective of the specific reasons for the deaths, covering mortality from all possible causes. |
| Time to Reach a Negative Event | 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 ECMO, and respiratory HFO2. Only the first occurrence of any event up to day 28 was considered for the analysis. Median and 95% CI estimates of survival time were based on the Kaplan-Meier analysis. |
| Time to Reach a Positive Event | Up to 28 days | Positive events were defined as the participants being officially discharged from hospital care by the department due to improvement in participant condition (self-discharge by participant was not considered a positive event). |
| Change From Baseline in National Early Warning Score 2 (NEWS2) | Day 3, Day 7, Day 14, and Day 28 | The NEWS2 is based on a simple aggregating scoring system in which scores allocated to physiological measurements (e.g., respiratory rate, oxygen saturation, systolic blood pressure, heart rate, level of consciousness, and temperature) are added up together to provide the clinical status of a patient. The total score of NEWS2 is interpreted as follows: * 0 to 4: Low risk - Usually indicates the participant is stable, with no immediate cause for concern. * 5 to 6: Medium risk - Suggests the participant may require closer monitoring and further assessment. * 7 to 20: High risk - Indicates the participant is at significant risk of clinical deterioration and may require urgent medical intervention, including escalation of care to a higher level or immediate medical review. |
| Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Up to 90 days | An AE is any untoward medical occurrence associated with the use of a study medication in humans, whether or not considered study-medication-related. A TEAE was defined as an AE that occurred or worsened in the period from the first dose of study treatment to 30 days after the last dose of the IP. An AE was considered serious if it resulted in any of the following outcomes: death, life-threatening, caused inpatient hospitalization or prolonged existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital abnormality/birth defect, or was an important medical event. AE severity was rated according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death). |
| Number of Participants Experiencing TEAEs of Special Interest (EOI) | Up to 90 days | The TEAE of special interest in this study included documented events of orthostatic hypotension (OHT) with supine and standing blood pressure measurements, where OHT is defined as a drop in blood pressure from supine to standing position: * of ≥20 mmHg in systolic blood pressure (SBP), and/or * of ≥10 mmHg in diastolic blood pressure (DBP). |
Countries
Belgium, Brazil, France, Puerto Rico, United States
Contacts
PRINCIPAL_INVESTIGATORCapucine Morelot-Panzini, MD
Département R3S GHU APHP-Sorbonne Université, Pitié Salpetrière
Participant flow
Recruitment details
Participants were enrolled at 37 study centers in the following countries: United States (13 study centers), Belgium (3 study centers), Brazil (14 study centers), and France (7 study centers) between August 2020 and June 2022.
Pre-assignment details
Participants with coronavirus disease 2019 (COVID-19) were randomized in a 1:1 ratio to receive either BIO101, or the matching placebo. A total of 3 participants in the BIO101 group and 2 participants in the placebo group did not receive the first dose of study medication and therefore were not included in the analysis.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 63.0 years STANDARD_DEVIATION 9.82 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 60 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 41 Participants |
| Race/Ethnicity, Customized American Indian or Alaska native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 11 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other pacific islander | 0 Participants |
| Race/Ethnicity, Customized Not reported | 28 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Race/Ethnicity, Customized White or Caucasian | 86 Participants |
| Sex: Female, Male Female | 43 Participants |
| Sex: Female, Male Male | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 129 | 21 / 109 |
| other Total, other adverse events | 59 / 128 | 53 / 104 |
| serious Total, serious adverse events | 32 / 128 | 34 / 104 |
Outcome results
None listed