Testing the Efficacy and Safety of BIO101 for the Prevention of Respiratory Deterioration in COVID-19 Patients

The COVA clinical study is a global multicentric, double-blind, placebo-controlled, group sequential and adaptive 2 parts phase 2-3 study targeting in patients 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).

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 patients, 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 patients)

Eligibility Criteria:
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. Patients can be included even if treated with: oxygen supplementation, High-flow oxygen (HFO2), BiPAP and 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 subjects 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 subjects 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 subject 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 subjects 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. Patient on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO)
4. Patient 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. Patient 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