Clinical Trials Register

Summary
EudraCT Number:	2020-001605-23
Sponsor's Protocol Code Number:	HUA-COVID-19
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-05-31
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

Spain - AEMPS

A.2

EudraCT number

2020-001605-23

A.3

Full title of the trial

Effectiveness of the combined treatment with hydroxycloroquine and azithromycin vs lopinavir/ritonavir + hydroxycloroquine in hospitalized patients with confirmed COVID-19 infection

Efectividad de hidroxicloroquina + azitromicina vs lopinavir/ritonavir +hidroxicloroquina en pacientes hospitalizados por COVID-19

A.3.1

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

Effectiveness of the combined treatment with hydroxycloroquine and azithromycin vs lopinavir/ritonavir + hydroxycloroquine in hospitalized patients with confirmed COVID-19 infection

Efectividad de hidroxicloroquina + azitromicina vs lopinavir/ritonavir + hidroxicloroquina en pacientes hospitalizados por COVID-19

A.4.1

Sponsor's protocol code number

HUA-COVID-19

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	Basque Health Service
B.1.3.4	Country	Spain
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	Basque Health Service
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Investigation Institute Bioaraba
B.5.2	Functional name of contact point	Inés Pérez Francisco
B.5.3	Address:
B.5.3.1	Street Address	C/José Atxotegui
B.5.3.2	Town/ city	Vitoria-Gasteiz
B.5.3.3	Post code	01009
B.5.3.4	Country	Spain
B.5.6	E-mail	INES.PEREZFRANCISCO@osakidetza.eus

D. IMP Identification
D.IMP: 1
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	Lopinavir/Ritonavir Accord
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorios Accord S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.8	INN - Proposed INN	LOPINAVIR
D.3.9.1	CAS number	192725-17-0
D.3.9.4	EV Substance Code	SUB02970MIG
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITONAVIR
D.3.9.1	CAS number	155213-67-5
D.3.9.4	EV Substance Code	SUB10342MIG
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	50
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	Dolquine
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorios Rubió S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.8	INN - Proposed INN	HYDROXYCHLOROQUINE
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: 3
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	Zitromax
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.8	INN - Proposed INN	AZITHROMYCIN DIHYDRATE
D.3.9.3	Other descriptive name	AZITHROMYCIN
D.3.9.4	EV Substance Code	SUB16399MIG
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	500
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

Covid-19 infection

Infección por Covid-19

E.1.1.1

Medical condition in easily understood language

Covid-19 infection

Infección por 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 compare the proportion of patients with COVID-19 infection who achieve a score of less than 2 on the Brescia-COVID respiratory severity scale after treatment with hidroxycloroquine + azithromycin versus actual practice

En pacientes con infección por COVID-19, comparar la proporción de sujetos que alcanzan puntuación menor que 2 en la escala de gravedad respiratoria Brescia-COVID con el tratamiento hidroxicloroquina + azitromicina frente al tratamiento habitual con lopinavir/ritonavir/hidroxicloroquina

E.2.2

Secondary objectives of the trial

- Time to reach a score lower than 2 on the Brescia-COVID respiratory severity scale.
- Proportion of subjects who die and time to death.
- Subject ratio (negative PCR) at the end of the treatment and time until denial.
- Proportion of subjects admitted to the ICU, time until admission to the ICU and length os stay.
- Duration of the hospital discharge.
- Time until intubation or invasive mechanical ventilation.
- Duration of the invasive mechanical ventilation.
- Proportion of subjects with adverse effects associated with the received treatment.

Comparación entre ambos grupos de:
- Tiempo hasta alcanzar una puntuación menor que 2 en la escala de gravedad respiratoria Brecia-COVID.
- Proporción de sujetos (PCR negativa y ct-PCR) al final del tratamiento y tiempo hasta la negativización.
- Proporción de sujetos ingresados en UCI, tiempo hasta ingreso en UCI y duración de la estancia.
- Duración de la estancia hospitalaria y tiempo hasta alta hospitalaria.
- Proporción de sujetos que fallecen y tiempo hasta fallecimiento.
- Proporción de sujetos con efectos adversos asociados al tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- RT-PCR confirmed.
- 18-80 years.
- Pneumonia confirmed by Rx chest: pneumonia CURB<=1 y Sat O2>92%

-RT-PCR positivo
- entre 18 y 80 años
- con neumonía confirmada mediante Rx toral: neumonía CURB<=1 y Sat O2 <92%

E.4

Principal exclusion criteria

->7 days from the onset of symptoms
- Severe disease Covid 19, defined by any of the following: FR<30 per min, sat O2 breathing ambient air<92%, sepsis or septic shock
- Pregnancy
- Kidney or liver terminal disease
- History of allergy to hydroxycloroquine and/or azithromycin
- Patients presenting contraindications to study drugs
- Hyprsensitivity to azithromycin, erythromycin, to any other macrolide or ketolide antibioticor any of the following excipients: pregelatinized corn starch, sodium crocarmellose, sodium laurel sulfate, magnesium stearate, anhydrous calcium hydrogen phosphate, hypromellose, titanium dioxide (E-171), triacetin.
- Electrocardiographic abnormalities: treatment is not started or discontinued if QTc (Brazett formula)>500ms and risk-benefit is valued between a460-500 ms. Does not start treatment if ECG shows changes in channel-patties and risk-benefit is valued if there are other abnormalities.
- Patients with glucose 6 phosphate dehydrogenase deficiency.

- > 7 días de inicio de los síntomas.
- Enfermedad por COVID-19 grave, definida por cualquiera de los siguientes: FR>30 por minuto, saturación de O2 respirando aire ambiente <92%, sepáis o shock séptico.
- Embarazo
- Enfermedad renal o hepática terminal
- Antecedentes de alergia a hidroxicloroquina y/o azitromicina o anafilaxia
- Pacientes que presenten contraindicaciones a los medicamentos del estudio
- Hipersensibilidad a azitromicina, eritromicina, a cualquier otro antibiótico macrólido o ketólido o a alguno de los siguientes excipientes: almidonesón de maíz pregelatinizado, almidón de maíz, croscarmelosa sódica, laurilsulfato de sodio, estrato de magnesio, hidrogenofosfato de calcio anhidro, hipromelosa, dióxido de titanio (E-171), triacetina.
- Alteraciones electrocardiográficas: no se comienza tratamiento o se discontinua si QTc (formula Brazett)>500 ms y se valora riesgo-beneficio entre 460 y 500 ms. No se inicia tratamiento si ECG muestras alteraciones de canalopatías y se valora riesgo-beneficio si hay otras anormalidades.
- Pacientes con deficit de glucosa 6 fosfato

E.5 End points

E.5.1

Primary end point(s)

Respiratory severity scale Brescia-COVID

Escala de severidad respiratoria Brescia-COVID

E.5.1.1

Timepoint(s) of evaluation of this end point

During hospital admission

Durante ingreso hospitalario

E.5.2

Secondary end point(s)

- Mortality from any cause and time until the death
- Days when punctuation in Brescia scale <2
- Length of hospital stay
- Time until intubation or invasive ventilation
- Invasive ventilation duration time
- Adverse effects
- ct-PCR SARS-Cov-2: 7, 14 and 21 days from start of treatment
- Time until admission to ICU and duration of stay in ICU
- Hospital discharge and time to hospital discharge
- Age
- Sex
- Comorbidity

- Muerte de cualquier causa y tiempo hasta fallecimiento
- Días que la puntuación en el escala Brescia se mantiene <2
- Duración de la estancia hospitalaria
- Tiempo hasta incubación o ventilación invasiva
- Tiempo de duración de la ventilación invasiva
- Efectos adversos
- ct-PCR SARS-Cov-2: 7, 14 y 21 días desde el inicio de tratamiento
- Ingreso en UCI: tiempo hasta ingreso y duración de estancia en UCI
- Alta hospitalaria y tiempo hasta alta hospitalaria
- Edad
- Sexo
- Comorbilidades

E.5.2.1

Timepoint(s) of evaluation of this end point

During hospital admission

Durante ingreso hospitalario

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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.8.5

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

Not apply

No aplica

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:

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

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The patients will give oral consent

Los pacientes darán consentimiento oral

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

108

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

Ninguno

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

2020-05-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-05-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-10-05

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