Clinical Trials Register

Summary
EudraCT Number:	2020-001892-34
Sponsor's Protocol Code Number:	PI20208430041
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-04-22
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

France - ANSM

A.2

EudraCT number

2020-001892-34

A.3

Full title of the trial

Treatment of COVID-19 by Nebulization of Inteferon Beta 1b added to lopinavir/ritonavir: Feasibility, Efficiency and Safety Study

Traitement du COVID-19 : Etude de faisabilité, d’efficacité et de sécurité de l’ajout de Nébubilisation d’Interferon Beta 1b au lopinavir/ritonavir

A.3.1

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

Treatment of COVID-19 by Nebulization of Inteferon Beta 1b added to lopinavir/ritonavir: Feasibility, Efficiency and Safety Study

Traitement du COVID-19 : Etude de faisabilité, d’efficacité et de sécurité de l’ajout de Nébubilisation d’Interferon Beta 1b au lopinavir/ritonavir

A.3.2

Name or abbreviated title of the trial where available

COV-NI

A.4.1

Sponsor's protocol code number

PI20208430041

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	CHU Amiens-Picardie
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	CHU Amiens
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	CHU Amiens Picardie
B.5.2	Functional name of contact point	Annabelle Boussault
B.5.3	Address:
B.5.3.1	Street Address	1 rond point du Pr Cabrol
B.5.3.2	Town/ city	Amiens
B.5.3.3	Post code	80054
B.5.3.4	Country	France
B.5.4	Telephone number	032203220883698369
B.5.5	Fax number	032203220896459645
B.5.6	E-mail	boussault.annabelle@chu-amiens.fr

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	Yes
D.2.1.1.1	Trade name	Extavia
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Inteferon Beta 1b
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
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.IMP: 2
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	Yes
D.2.1.1.1	Trade name	Lopinavir/Ritonavir Mylan
D.2.1.1.2	Name of the Marketing Authorisation holder	Mylan SAS
D.2.1.2	Country which granted the Marketing Authorisation	France
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	lopinavir/ritonavir
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	NaCl
D.2.1.1.2	Name of the Marketing Authorisation holder	Aguettant
D.2.1.2	Country which granted the Marketing Authorisation	France
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	NaCl
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Infection SARS-Cov-2

E.1.1.1

Medical condition in easily understood language

covid 19

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

to evaluate the virological efficacy of the addition of inhaled Interferon-β-1 b compared to the control arm in patients hospitalized with COVID-19.

Evaluer l'efficacité virologique de l’ajout d’Interféron-β-1 b administré par voie inhalée par rapport au bras témoin chez les patients hospitalisés avec COVID-19.

E.2.2

Secondary objectives of the trial

To evaluate the overall clinical efficacy and safety of inhaled Interferon-β-1 b versus the control arm in patients hospitalized with COVID-19

Comparison between the two arms of :
Time to viral negativation on PCR.
Evolution of the NEW score at D15.
Evolution of oxygen needs.
Time of recourse to oxygen therapy or mechanical ventilation support.
Evolution of biological parameters: inflammation, liver enzymes, kidney function
Mortality at J28.
Length of stay (post-inclusion).

Evaluer l'efficacité clinique globale et la tolérance de l’Interféron-β-1 b administré par voie inhalée par rapport au bras témoin chez les patients hospitalisés avec COVID-19
Comparaison entre les deux bras de :
Temps de négativation virale à la PCR.
Evolution du NEW score à J15.
Evolution des besoins en oxygène.
Temps de recours à l’oxygnothérapie ou au support de ventilation mécanique
Evolution des paramètres biologiques : inflammation, enzymes hépatiques, fonction rénale
Mortalité à J28.
Durée de séjour (post-inclusion).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age ≥ 18 years old
Patient with laboratory-confirmed SARS-CoV-2 infection by PCR < 96 h (at initial diagnosis or aggravation phase with persistent carriage <96 h)
Inpatients with COVID-19 of any duration, requiring oxygen therapy (mask or mechanical ventilation).
Social security coverage
Having signed an informed consent (or his or her legally authorized representative).

Age ≥ 18 ans
Patient présentant une infection au SARS-CoV-2 confirmée en laboratoire, par PCR < 96 h (au diagnostic initial ou phase d’aggravation avec portage persistant <96 h)
Patients hospitalisés souffrant du COVID-19 de n'importe quelle durée, et nécessitant une l’oxygénothérapie (masque ou une ventilation mécanique).
Couverture par la sécurité sociale
Ayant signé un consentement éclairé (ou son représentant légalement autorisé à le représenter).

E.4

Principal exclusion criteria

- Hypersensitivity to natural or recombinant interferon-ß
- Hypersensitivity to human albumin or mannitol
- Hypersensitivity to lopinavir/ritonavir
- Recent suicide attempt
- Decompensation of liver failure
- Pregnant or breastfeeding woman.
- Patients treated on an outpatient basis (i.e. not initially hospitalized).
- Parenteral NFI treatment.
- Concomitant use of drugs that are contraindicated with lopinavir/ritonavir, i.e. drugs whose metabolism is highly dependent on the CYP3A isoform with a narrow therapeutic range (e.g. amiodarone, colchicine, simvastatin).
- Patient under guardianship, curatorship or safeguarding of justice

Translated with www.DeepL.com/Translator (free version)

- Hypersensibilité à l'interféron ß naturel ou recombinant
- Hypersensibilité à l'albumine humaine ou mannitol
- Hypersensibilité au lopinavir/ritonavir
- Tentative de suicide récente
- Décompensation d'une insuffisance hépatique
- Femme enceinte ou allaitante.
- Patients pris en charge en soins ambulatoires (c'est-à-dire non hospitalisés initialement).
- Traitement par IFN par voie parentérale.
- Utilisation concomittante de médicaments qui sont contre-indiqués avec le lopinavir/ritonavir, c'est-à-dire des médicaments dont le métabolisme est fortement dépendant de l'isoforme CYP3A avec une marge thérapeutique étroite (par exemple amiodarone, colchicine, simvastatine).
- Patient sous tutelle, curatelle ou sauvegarde de justice

E.5 End points

E.5.1

Primary end point(s)

sustained viral negativation time D3-7-11-15

temps de négativation virale soutenue J3-7-11-15

E.5.1.1

Timepoint(s) of evaluation of this end point

D3-D7-D11-D15

J3-7-11-15

E.5.2

Secondary end point(s)

Tolerance and safety (no major adverse effects expected by drastic reduction of systemic passage):
- Collection of grade 3 or 4 serious adverse events (frequency)
- Cumulative incidence of Grade 3 or 4 adverse events.

Clinical Course :
- Clinical evolution by variation of the ordinal severity scale from 7 points to D15 (Appendix 4)
- Time to decrease the ordinal scale of severity by one category relative to intake.
- Evolution of the NEW score at D15 (Appendix 5)
- Evolution of oxygen requirements (6-point scale)
- Time without a mechanical fan (days) over the first 16 days (median)
- Oxygen-free time over the first 16 days (median).
- Number of ventral decubitus positions (protocolized for 18-hour durations).
- Time for normalization of fever.

- Evolution of biological parameters: inflammation, liver enzymes, renal function...
- Routine biochemistry and haematology assay at the CHU of Amiens
- Standard inflammation (NFS, CRP, PCT)
- kidney function (creatine)
- Liver function (liver enzymes, LDH, AST/ALAT, bilirubin)
- Immunoassay (IL6, IL8, TNF-α, IL1b, IL-10, IFN gamma, IFN type I)

- Mortality at J28.
- Length of stay in intensive care (post-inclusion).
- Length of stay in hospital (post-inclusion).

Tolérance et sécurité (pas d’effets indésirables majeurs attendus par réduction drastique du passage systémique).
- Recueil d’effets indésirables grave de grade 3 ou 4 (fréquence)
- Incidence cumulée des effets indésirables de grade 3 ou 4.

Evolution clinique
- Evolution clinique par variation de l’échelle ordinale de gravité de 7 points à J15 (Annexe 4)
- Temps pour diminuer d’une catégorie l’échelle ordinale de gravité par rapport à l’admission.
- Evolution du NEW score à J15 (Annexe 5)
- Evolution des besoins en oxygène (échelle à 6 points)
- Temps sans ventilateur mécanique (en jours) sur 16 premiers jours (médiane)
- Temps sans besoin d’oxygène sur 16 premiers jours (médiane).
- Nombre de décubitus ventraux (protocolisé pour des durées de 18h).
- Temps pour normalisation de la fièvre.

- Evolution des paramètres biologiques : inflammation, enzymes hépatiques, fonction rénale
• Dosage de routine de biochimie et d’hématologie du CHU d’Amiens
• Inflammation standard (NFS, CRP, PCT)
• fonction rénale (créatine)
• fonction hépatique (enzymes hépatique, LDH, ASAT / ALAT, bilirubine)
• Dosage immunologique (IL6, IL8, TNF-α, IL1b, IL-10, IFN gamma, IFN de type I)

- Mortalité à J28.
- Durée de séjour en réanimation (post-inclusion).
- Durée de séjour à l’hôpital (post-inclusion).

E.5.2.1

Timepoint(s) of evaluation of this end point

28 days

28 jours

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

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

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	30
F.1.3	Elderly (>=65 years)	No
F.1.3.1	Number of subjects for this age range:	30
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	No
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	No
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	Yes
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	60

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

2020-06-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-24

P. End of Trial
P.	End of Trial Status	Completed

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