Clinical Trials Register

Summary
EudraCT Number:	2020-001406-27
Sponsor's Protocol Code Number:	RECHMPL20-168
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-04-03
Trial results	View 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

2020-001406-27

A.3

Full title of the trial

Randomized open label trial assessing efficacy and safety of hydroxychloroquine plus azithromycin versus hydroxychloroquine for hospitalized patients with COVID-19

Etude multicentrique, randomisée, de l’efficacité et la sécurité de la Bithérapie Hydroxychloroquine + Azithromycine comparée à une Monothérapie par Hydroxychloroquine chez des adultes hospitalisés pour une infection COVID-19 avec une pneumonie non réanimatoire

A.3.1

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

efficacy and safety of a bitherapy by hydroxychloroquine + azythromycin vs monotherapy by hydroxychoroquine in adult patients with documentated infection by covid19

A.4.1

Sponsor's protocol code number

RECHMPL20-168

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	University Hospital of Montpellier
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	DGOS
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	University hospital of Montpellier
B.5.2	Functional name of contact point	Claire CHAUVETON
B.5.3	Address:
B.5.3.1	Street Address	191 avenue du Doyen Gaston Giraud
B.5.3.2	Town/ city	Montpellier
B.5.3.3	Post code	34295
B.5.3.4	Country	France
B.5.4	Telephone number	00330608492834
B.5.5	Fax number	0033467339172
B.5.6	E-mail	depotAC@chu-montpellier.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	plaquenil
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Aventis
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.3.4	Pharmaceutical form	Tablet
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.3.9.1	CAS number	747-36-4
D.3.9.3	Other descriptive name	HYDROXYCHLOROQUINE SULFATE
D.3.9.4	EV Substance Code	SUB02587MIG
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	200
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	azithromycin
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz
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	azithromycine
D.3.4	Pharmaceutical form	Tablet
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.3.9.1	CAS number	121470-24-4
D.3.9.3	Other descriptive name	AZITHROMYCIN MONOHYDRATE
D.3.9.4	EV Substance Code	SUB87696
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	250
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

infection COVID 19

E.1.1.1

Medical condition in easily understood language

infection 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

Evaluation of efficacy of a bitherapy by hydroxychloroquine + azythromycin vs monotherapy by hydroxychoroquine administered for 10 days, on patient infected with SarS COV 2 with either a moderate clinical form (level 3), or a severe non-resuscitative clinical form (level 4)

Evaluer l’efficacité d’une bithérapie hydroxychloroquine-azithromycine administrée pendant 10 jours, comparativement à l’hydroxychloroquine seule, sur l’amélioration clinique à J11 d’au moins un niveau selon une échelle ordinale (échelle utilisée dans l’essai Discovery NCT04315948), chez des adultes hospitalisés pour une infection COVID-19 de gravité moyenne (hospitalisation sans oxygénothérapie : niveau 3) ou sévère (hospitalisation avec oxygénothérapie hors réanimation : niveau 4)

E.2.2

Secondary objectives of the trial

- Evaluation of the safety of a bitherapy by hydroxychloroquine + azythromycin vs monotherapy by hydroxychoroquine
- Need of oxygenotherapy
- virological, and pharmacokinetic assessment of each treatment
-PAtient transfer in ICU.
- hospitalization duration
Vital status
Adverses event

Efficacité clinique
Evolution (amélioration, stabilité, progression) de l’état clinique sur échelle 7 niveaux à J3, J5, J8, J11, J 15 et J29
Evolution du Score NEWS à J3, J5, J8, J11, J 15 et J29
Evolution variables physiologiques (température, fréquence respiratoire)
Evolution des images radiologiques pulmonaires entre J1 et J11
Nécessité et durée oxygénothérapie
Nécessité de transfert en réanimation
Nécessité ventilation mécanique
Durée hospitalisation (jours)
Mortalité hospitalière et à J29
Sécurité et tolérance
Incidence des événements indésirables sérieux
Incidence des événements rattachés aux traitements
Incidence des anomalies biologiques
Evolution de l’espace QTc en cours de traitement (ECG de surveillance à J2, J3, J5, J8 J11)
Arrêt prématuré des traitements de l’étude
Evaluation virologique (PCR qualitative et quantitative) et immunologique à J5, J10, J15
Evaluation pharmacocinétique à J3, J8 et J11

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

immunological assessment of the effect of the experimental treatment (only in Montpellier Hospital)

E.3

Principal inclusion criteria

Written informed consent
Adult under 75 years old
- documented infection with SARS CoV 2 (positive virological test) within 96 h before randomization
- COVID-19 symptoms occurring within 10 days of randomization
- Radiographic or tomography signs of pneumonia (infiltrates)
- Hospitalized patient (outside the intensive care unit) with either a moderate clinical form (defined as not requiring oxygen therapy at the time of randomization), or a severe non-resuscitative clinical form (defined as requiring oxygen therapy by nasal tube or mask with an oxygen flow <6 l / min)

- Etre capable de, et être disposé(e) à fournir un consentement éclairé écrit avant la réalisation des procédures de l’étendue
- Age d’au moins 18 ans et de 75 ans au plus
- Infection par le SARS-CoV-2, documentée par un test virologique positif dans les 96 h précédent la randomisation
- Début des symptômes de COVID-19 datant de moins de 10 jours au moment de la randomisation
- Présence de symptôme(s) de COVID-19 : fièvre (température  37,5°C) ou signe(s) respiratoires (toux, gêne respiratoire) ou anosmie récente (perte de l’odorat)
- Présence de signes radiographiques ou tomodensitométriques de pneumonie (infiltrats)
- Hospitalisation hors unité de réanimation pour un COVID-19 avec soit une forme clinique modérée (définie comme ne nécessitant pas au moment de la randomisation une oxygénothérapie), soit une forme clinique sévère non réanimatoire ( définie comme nécessitant une oxygénothérapie par sonde nasale ou masque avec un débit d’oxygène < 6 l/min)

E.4

Principal exclusion criteria

-- admission to intensive care at the time of selection
- contraindication to IMPs
Oxygen saturation rate low defined as
- <90% in ambient air
- <94% with oxygen therapy  3 l / min
need for oxygen therapy≥ 6 l / min or mechanical ventilation
ALT or ASAT rate> 5 LSN
renal failure (DGFe <30 ml / min) or dialysis
Pregnancy or breastfeeding
Retinopathy
Known G6PD deficiency
History of heart rhythm disorder or QT prolongation
Prolongation of the QT space on an ECG dating at the time of selection of less than 24 hours: QTc> 450 ms
- hydoxychloroquine contra indication (citalopram, escitalopram, hydroxyzine, domperidone and piperaquine);
- Taking drugs known to prolong the QT interval or likely to induce a cardiac arrhythmia such as anti-arrhythmics of class IA and III, tricyclic antidepressants, antipsychotics
- Participation in another clinical trial with an experimental treatment of COVID-19
- A Concomitant treatment with possible action on SARS-CoV-2 is not authorized if it is administered less than 24 hours before the administration of the IMP

Les patient(e)s qui remplissent l’un des critères suivants ne doivent être inclus dans l’étude :
Taux de saturation en oxygène (SaO2 par gazométrie artérielle ou SpO2 par saturomètre-oxymètre de pouls) bas défini comme
< 90 % en air ambiant
< 94 % avec une oxygénothérapie  3 l/min
Nécessité d’une oxygénothérapie ≥ 6 l/min ou d’une ventilation mécanique
Nécessité d’une admission en réanimation au moment de la sélection
Anticipation d’un séjour dans un service hospitalier ne participant pas à l’essai dans un délai inférieur à 3 jours
Taux d’ALAT ou d’ASAT > 5 LSN
insuffisance rénale (DGFe < 30 ml/min ) ou dialyse
Grossesse ou allaitement
Rétinopathie
Déficit connu en G6PD
Antécédents de troubles du rythme cardiaque ou d’allongement QT
Allongement de l’espace QT sur un ECG datant au moment de la sélection de moins de 24h: QTc > 450 ms
Prise de médicaments contre-indiqués avec la prise d’hydoxychloroquine (citalopram, escitalopram, hydroxyzine, la dompéridone et la pipéraquine) ;
Prise de médicaments connus pour allonger l'intervalle QT ou susceptibles d'induire une arythmie cardiaque comme par exemple les anti-arythmiques de classe IA et III, les antidépresseurs tricycliques, les antipsychotiques
Participation à un autre essai clinique portant sur un traitement expérimental du COVID-19
Prise d'un autre traitement ayant une action possible sur le SARS-CoV-2 dans les 24 h avant la randomisation

E.5 End points

E.5.1

Primary end point(s)

At least 1 level improvement in clinical status assessed by a level ordinal scale (at least 1 level) between D1 and D11 :
1. Not hospitalized, no limitation of activities
2. Not hospitalized, limitation of activities;
3. Hospitalized, not requiring oxygen supplementation
4. Hospitalized, requiring oxygen supplementation
5. Hospitalized, non-invasive ventilation or high flow oxygen device
6. Hospitalized, under invasive mechanical ventilation or ECMO (extracorporeal membrane oxygenation)
7. Death

temps jusqu’à l’amélioration clinique d’au moins un niveau selon une échelle ordinale à partir de J1 (jour de la première administration des médicaments de l’étude) jusqu’à J11 (lendemain du dernier jour du traitement).
1. Non hospitalisé, aucune limitation des activités
2. Non hospitalisé, limitation des activités;
3. Hospitalisé, ne nécessitant pas de supplémentation en oxygène
4. Hospitalisé, nécessitant une supplémentation en oxygène
5. Hospitalisé, sous ventilation non invasive ou dispositif à oxygène haut débit
6. Hospitalisé, sous ventilation mécanique invasive ou ECMO
7. Mort

E.5.1.1

Timepoint(s) of evaluation of this end point

D11

E.5.2

Secondary end point(s)

1.clinical status
2.variation of clinical and respiratory parameter
3.Adverse event
4.Virological (qualitative and quantitative PCR) and immunological evaluation at D5, D10, D15
5.pharmacokinetic evaluation at D3 D5 D8 and D11
6. oxygenotherapy duration
7. Hospitalization duration
8 mortality
9. ICU transfer
10 QTc prolongation
11.Variation of pulmonary CT images between D1 and D11, with centralized blind analysis by independent expert reader

E.5.2.1

Timepoint(s) of evaluation of this end point

1.Day 3, 5,7, 11, 15, 29
2. up to Day 29
3. up to Day 29
4. Day 5, D10 and D15
5. D3 D5 D8 and D11
6. up to D15
8. up to D 29
9. up to D29
10. D2, D3 D5, D8, D11
11 D11

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

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

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

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

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:

110

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

120

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)

none

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

2020-04-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-07

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-06-08

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