Clinical Trials Register

Summary
EudraCT Number:	2020-001498-63
Sponsor's Protocol Code Number:	BIO101-CL05
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-05-03
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2020-001498-63

A.3

Full title of the trial

Adaptive design phase 2 to 3, randomized, double- blind, multicenter, to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics of BIO101 in the prevention of the respiratory deterioration in hospitalized patients with COVID-19 pneumonia (severe stage)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

BIO101-CL05

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Biophytis S.A.
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Biophytis S.A.
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Biophytis S.A.
B.5.2	Functional name of contact point	Mounia Chabane De Saint Aubin
B.5.3	Address:
B.5.3.1	Street Address	14 Avenue de l' Opéra
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75001
B.5.3.4	Country	France
B.5.4	Telephone number	+33(0)144 27 23 87
B.5.6	E-mail	mounia.chabane@biophytis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	BIO101
D.3.2	Product code	BIO101
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	5289-74-7
D.3.9.2	Current sponsor code	BIO101
D.3.9.3	Other descriptive name	20-hydroxyecdysone
D.3.9.4	EV Substance Code	SUB193629
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	175
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Confirmed infection with SARS-CoV-2 (COVID-19)

E.1.1.1

Medical condition in easily understood language

Corona virus (COVID-19)

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10047465
E.1.2	Term	Viral infections NEC
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	PT
E.1.2	Classification code	10084268
E.1.2	Term	COVID-19
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part 1
• Ascertain the safety and tolerability of BIO101, in order to facilitate recruitment to part 2
• Obtain preliminary indication of activity of BIO101, in preventing respiratory deterioration in the target population

Part 2
• Re-assess the sample size that is needed for the confirmatory part of the study
• Provide confirmation on the benefit of BIO101 in the target population
• Identify and assess potential biomarkers for further understanding of the effect of BIO101 in the target population

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age: 45 and older.
2. Modified per Amendment 10:
2.1 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. Modified per Amendment 10:
4.1 With evidence of pneumonia based on all of the following:
a. Clinical findings on a physical examination
b. Respiratory symptoms developed within the past 14 days
5. Modified per Amendment 10:
5.1 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:
a. Tachypnea: ≥25 breaths per minute
b. Arterial oxygen saturation ≤92%
c. 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:
a. ALT and AST ≤ 5x upper limit of normal (ULN)
b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN
c. Total bilirubin ≤ 5×ULN
7. Willing to participate and able to sign an informed consent form (ICF).Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant
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
a. Have a negative urine pregnancy test at screening
b. 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. Female participant who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention.
11. 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;
12. Inclusion criterion 12 removed per Amendment 10.

E.4

Principal 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 not able to take medications by mouth (as capsules or as a powder, mixed in water).
5. 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)
6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101
7. Exclusion criterion 7 removed per Amendment 10
8. Exclusion Criterion 8 removed per Amendment 10

E.5 End points

E.5.1

Primary end point(s)

For end-of-part-1 interim analysis:

For safety analysis intended to facilitate recruitment for part 2, time frame – up to 28 days:

Safety and tolerability to BIO101:

• SUSARs, SAEs, AESIs, AEs
• Vital signs
• Safety labs (including testicular biomarkers)
• ECGs

For interim analysis intended to obtain indication of activity of BIO101, time frame – up to 28 days:

Primary:

• Proportion of participants with ‘negative’ events, of either of the following:
o All-cause mortality
o 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

Secondary:

• SpO2/FiO2
• Inflammatory markers including:
o IL 6
o TNFα
o D-dimer
• RAS / MAS biomarkers:
o Angiotensin 2
o Angiotensin 1-7 (Ang (1-7)
o Angiotensin 1-5 (Ang 1-5)
o Angiotensin 1
o Angiotensin-converting enzyme 2(ACE2) levels and activity

For part-2 sample size interim analysis:

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:
o All-cause mortality
o 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:

Primary, time frame – up to 28 days:

• Proportion of participants with ‘negative’ events, of either of the following:
o All-cause mortality
o 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

E.5.1.1

Timepoint(s) of evaluation of this end point

For end-of-part-1 interim analysis:
For safety analysis intended to facilitate recruitment for part 2, time frame – up to 28 days:

For interim analysis intended to obtain indication of activity of BIO101, time frame – up to 28 days:

For part-2 sample size interim analysis:
For sample size re-assessment for part 2, time frame – up to 28 days:

For the final analysis:
Primary, time frame – up to 28 days:

E.5.2

Secondary end point(s)

Key secondary:
• Proportion of participants with ‘positive’ events:
o official discharge from hospital care by the department due to improvement in participant condition (self-discharge by particpant is not considered a positive event)

Additional secondary endpoints:
• SpO2/FiO2
• Oxygen saturation in arterial blood, measured by pulse-oximetry (SpO2)
• Proportion of participants with events of all-cause mortality
• Time to events, of either of the following:
o All-cause mortality
o 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

• Time to event: official discharge from hospital care due to improvement
• The National Early Warning Score 2 (NewS2)
• Population-PK study (pop-PK)

Secondary Endpoints to Assess Durability of Effect:
• For participants who experienced a ‘positive’ event:
o Proportion of participants with the occurrence of negative event,
within the 14-day post intervention and 28- and 90-day postrandomization
time frame.
o Time to event: occurrence of a negative event during the 28- and
90 day period.
o Proportion of participants with sustained positive outcome, within
the 14-day post intervention and 28- and 90-day postrandomization
time frame.
o Time to event: official discharge from hospital-care due to
improvement without re hospitalization or death during the 28-
and 90 day period.
• For participants who experienced a ‘negative’ event:
o Proportion of participants with sustained positive outcome, within
the 14-day post intervention and 28- and 90-day postrandomization
time frame.
o Time to event: resolution of a negative event during the 28- and 90
day period.
o Proportion of participants with sustained positive outcome, within
the 14-day post intervention and 28- and 90-day postrandomization
time frame.
o Time to event: official discharge from hospital-care due to
improvement without re hospitalization or death during the 28-
and 90 day period.

E.5.2.1

Timepoint(s) of evaluation of this end point

During the trial

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

placebo-controlled, group sequential and adaptive

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Brazil

United States

Belgium

France

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

200

F.4.2.2

In the whole clinical trial

465

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

see protocol

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-05-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-05-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-06-06

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