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

Adaptive Design Phase 2 to 3, Randomized, Double-blind, to Evaluate Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of BIO101 in the Prevention of the Respiratory Deterioration in Hospitalized 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).

Study Overview

• Status: Terminated
• Conditions: Covid-19; SARS-CoV2
• Intervention / Treatment: Drug: Placebo; Drug: BIO101

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 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)

• Study Type: Interventional
• Enrollment (Actual): 238
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium
    • CHU Saint-Pierre
  • Brussels, Belgium
    • CHU Saint-Pierre
  • Mechelen, Belgium, 2800
    • AZ-Sint Maarten
  • Namur, Belgium, 15 5000
    • CHU CLU Namur (Saint-Elisabeth) Place Louise Godin
• Brazil
  • São Paulo, Brazil, 103.034
    • Avenida Dr. Enéas de Carvalho Aguiar, 44 - Centro de Pesquisa Clínica Prof. Dr. Fúlvio Pileggi - Bloco 1 - 1º Andar
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil
      • Hospital Vera Cruz
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil
      • Santa Casa de Porto Alegre
  • São Paulo
    • Barueri, São Paulo, Brazil
      • Hospital Municipal de Barueri Dr. Francisco Moran
    • Campinas, São Paulo, Brazil
      • Hospital e Maternidade Celso Pierro - PUCCAMP
    • São José Do Rio Preto, São Paulo, Brazil
      • Hospital de Base da Faculdade de Medicina de São José do Rio Preto
• France
  • Argenteuil, France
    • Centre Hospitalier Argenteuil
  • Bordeaux, France
    • Centre Hospitalier Universitaire Bordeaux
  • Cergy-Pontoise, France
    • Centre Hospitalier René Dubos
  • La Roche-sur-Yon, France
    • Centre Hospitalier Départemental de Vendée
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière, 47 bd de l'Hôpital, 75013 Paris
  • Paris Cedex 13
    • Paris, Paris Cedex 13, France, 75651
      • Unité ambulatoire Service de Pneumologie, Médecine Intensive et Réanimation (SPMIR) 47-83 Boulevard de l'Hôpital
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • FDI Clinical Research - San Juan City Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85015
      • Abrazo Health
  • California
    • Irvine, California, United States, 92697
      • University of California, Irvine
  • Louisiana
    • Natchitoches, Louisiana, United States, 71457
      • Barnum Medical Research, Inc. 1029 Keyser Ave Suite H
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Health
  • New York
    • Johnson City, New York, United States, 13903
      • United Health Services Hospitals
  • Pennsylvania
    • York, Pennsylvania, United States, 17403
      • WellSpan Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 41 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; placebo capsules; Other Names: Sarconeos (placebo)
Experimental: BIO101; BIO101 350 mg bid	Drug: BIO101; BIO101 capsules; Other Names: Sarconeos (BIO101)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
End-of-Part 1 interim analysis: Proportion of subjects with all cause mortality or with respiratory failure.	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	up to 28 days
For part-2 sample size interim analysis: Proportion of subjects with all cause mortality or with respiratory failure.	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	up to 28 days
For the final analysis: Proportion of subjects with all cause mortality or respiratory failure.	• 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	up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interim analysis; indication of activity of BIO101: Oxygen saturation by pulse oximetry (SpO2) SpO2 / Fraction of inspired oxygen (FiO2) ratio	• SpO2/FiO2	28 days
Interim analysis; indication of activity of BIO101: Inflammatory markers	• Inflammatory markers including: IL 6; TNFα; D-dimer	28 days
Interim analysis; indication of activity of BIO101: Renin Angiotensin System biomarkers	• Renin Angiotensin System biomarkers: Angiotensin 2; Angiotensin-converting enzyme (ACE) levels	28 days
Key secondary endpoint for final analysis: Proportion of participants with positive events	• official discharge from hospital care by the department due to improvement in participant condition (self-discharge by participant is not considered a positive event)	Up to 28 days
Additional secondary endpoints for final analysis: Respiratory function	Oxygen saturation in arterial blood, measured by pulse-oximetry (SpO2) SpO2/FiO2 Proportion of participants with CPAP/BiPAP events, defined as requiring CPAP/BiPAP/HFO2 in participants entering the study on low flow oxygen)	28 days
Additional secondary endpoints for final analysis:proportion of patients who experienced negative events	Time to 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; • Proportion of participants with CPAP/BiPAP/HFO2 events, defined as requiring CPAP/BiPAP/HFO2 in participants entering the study on low flow oxygen)	28 days
Additional secondary endpoint for final analysis: The National Early Warning Score 2 (NewS2):	National Early Warning Score 2 (NewS2): scores: 0-7	28 days
Additional secondary endpoint for final analysis: Population Pharmacokinetics study (pop-PK)	Cmax: Peak Plasma concentration	1day
Additional secondary endpoint : Population Pharmacokinetics study (pop-PK)	tmax: Time to reach peak plasma concentration	1 day
Additional secondary endpoint: Population Pharmacokinetics study (pop-PK)	AUC: Area under the plasma concentration versus time curve	1 day
Additional secondary endpoint: Proportion of participants with events of all-cause mortality	Proportion of participants with events of all-cause mortality	Up to 28 days
Additional secondary endpoint: time to event: negative events	Time to 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	Up to 28 days
Additional secondary endpoint: time to event: positive events	Time to event: official discharge from hospital care due to improvement	Up to 28 days

Collaborators and Investigators

• Sponsor: Biophytis
• Investigators: Principal Investigator: Capucine Morelot-Panzini, MD, Département R3S GHU APHP-Sorbonne Université, Pitié Salpetrière

Publications and helpful links

General Publications

• Dioh W, Chabane M, Tourette C, Azbekyan A, Morelot-Panzini C, Hajjar LA, Lins M, Nair GB, Whitehouse T, Mariani J, Latil M, Camelo S, Lafont R, Dilda PJ, Veillet S, Agus S. 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. Trials. 2021 Jan 11;22(1):42. doi: 10.1186/s13063-020-04998-5.

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2020
• Primary Completion (Actual): June 6, 2022
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: July 6, 2020
• First Submitted That Met QC Criteria: July 13, 2020
• First Posted (Actual): July 15, 2020

Study Record Updates

• Last Update Posted (Actual): May 15, 2023
• Last Update Submitted That Met QC Criteria: May 12, 2023
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: BIO101-CL05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No