Clinical Trials Register

Summary
EudraCT Number:	2020-001541-39
Sponsor's Protocol Code Number:	BEVACOR
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:	2020-04-27
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

2020-001541-39

A.3

Full title of the trial

Pilot study of single-dose bevacizumab as a treatment for acute respiratory distress syndrome in patients with COVID-19

Estudio piloto de bevacizumab dosis única como tratamiento del síndrome de distres respiratorio agudo en pacientes con COVID-19

A.3.1

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

Pilot study of bevacizumab as a treatment for respiratory distress in patients with COVID-19

Estudio de bevacizumab como tratamiento del distres respiratorio en pacientes con COVID-19

A.4.1

Sponsor's protocol code number

BEVACOR

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	Fundación para la Investigación Biomédica de Córdoba
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	FIBICO
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	Fundación para la Investigación Biomédica de Córdoba
B.5.2	Functional name of contact point	Antonio Luque
B.5.3	Address:
B.5.3.1	Street Address	Edificio IMIBIC - Avenida Menéndez Pidal s/n
B.5.3.2	Town/ city	Córdoba
B.5.3.3	Post code	14004
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034671596070
B.5.5	Fax number	0034957736571
B.5.6	E-mail	uicec@imibic.org

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	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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)	Yes
	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	Yes
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

Acute respiratory distress syndrome in patients with COVID-19

Síndrome de distres respiratorio agudo en pacientes con COVID-19

E.1.1.1

Medical condition in easily understood language

Acute respiratory diseasee in patients with COVID-19

Problemas respiratorios agudos en pacientes con 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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10001052
E.1.2	Term	Acute respiratory distress syndrome
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

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	10051905
E.1.2	Term	Coronavirus infection
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

- To evaluate the crude mortality rate at 28 days.

- Evaluar la tasa de mortalidad bruta a los 28 días.

E.2.2

Secondary objectives of the trial

- To evaluate the improvement in the PaO2 / FiO2 ratio at 24 hours, at 72 hours, at 7 days, 14 days and 28 days.
- To evaluate the improvement in the degree of dyspnea at 72 hours and at 7 days according to the Likert scale (-3 to +3).
- To evaluate the improvement of the radiological findings by (simple radiology) at 72 hours and at 7 days.
- To evaluate the improvement in transcutaneous O2 saturation at 24 hours, at 72 hours and at 7 days.
- To evaluate the improvement in PaO2.
- To measure the decrease in mortality (crude rate per month).
- To evaluate the toxicity of the established strategy.

- Evaluar la mejoría en el ratio PaO2/FiO2 a las 24 horas, a las 72 horas, a los 7 días, 14 días y 28 días.
- Evaluar la mejoría en el grado de disnea a las 72 horas y a los 7 días según la escala Likert (-3 a +3).
- Evaluar la mejoría de los hallazgos radiológicos por (radiología simple) a las 72 horas y a los 7 días.
- Evaluar la mejoría saturación de O2 transcutánea a las 24 horas, a las 72 horas y a los 7 días.
- Evaluar la mejoría en la PaO2.
- Medir la disminución de la mortalidad (tasa cruda al mes).
- Evaluar la toxicidad de la estrategia establecida.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 and <90 years
2. Diagnosis confirmed by COVID-19 PCR
3. Radiological image compatible with bilateral non-cardiogenic pleuropulmonary exudate
4. Having received antiviral and anti-inflammatory therapy according to the protocol of the Reina Sofía University Hospital in Córdoba
5. Present any of the following clinical-functional criteria:
5.a. Respiratory distress: Tachypnea> 30 breaths / minute
5.b. Partial arterial oxygen pressure (PaO2) / Inspiration fraction (FiO2) ≤ 300 mmHg
6. Signature of direct or delegated informed consent

1. Edad ≥ 18 y < 90 años
2. Diagnostico confirmado mediante PCR de COVID-19
3. Imagen radiológica compatible con exudado pleuropulmonar bilateral no cardiogénico
4. Haber recibido terapia antiviral y antiinflamatoria según protocolo de hospital Universitario Reina Sofía de Córdoba
5. Presentar alguno de los siguientes criterios clínico-funcionales:
5.a. Distres respiratorio: Taquipnea > 30 respiraciones/minuto
5.b. Presión Parcial arterial de oxigeno (PaO2)/Fracción de inspiración (FiO2) ≤ 300 mmHg
6. Firma de consentimiento informado directo o delegado

E.4

Principal exclusion criteria

1. Severe liver dysfunction (Child Pugh ≥ 3 or AST> 5 times normal)
2. Severe renal dysfunction with glomerular filtration <30 mL / minute or in treatment with hemodialysis or peritoneal dialysis)
3. Poorly controlled arterial hypertension (TAs> 160 mmHg or TAd <100 mmHg) or having a previous history of hypertensive crisis or hypertensive encephalopathy
4. History of poorly controlled heart disease with a NYHA> 2
5. History of thrombosis the previous 6 months
6. Signs of active bleeding
7. Open wounds, gastrointestinal perforation fractures
8. Diagnosis of thrombophilic diseases or bleeding diathesis
9. Active viral hepatitis or HIV not adequately treated
10. Intolerance or allergy to bevacizumab or its components
11. Pregnancy

1. Disfunción hepática grave (Child Pugh ≥ 3 o AST > 5 veces lo normal)
2. Disfunción renal severa con filtrado glomerular < 30 mL/minuto o en tratamiento con hemodiálisis o diálisis peritoneal)
3. Hipertensión arterial mal controlada (TAs > 160 mmHg o TAd <100 mmHg) o tener historia previa de crisis hipertensiva o encefalopatía hipertensiva
4. Historia de cardiopatía mal controlada con un NYHA > 2
5. Historia de trombosis los 6 meses previos
6. Signos de sangrado activo
7. Heridas abiertas, fracturas perforación gastrointestinal
8. Diagnóstico de enfermedades trombofílicas o de diátesis hemorrágica
9. Hepatitis vírica activa o VIH no tratados adecuadamente
10. Intolerancia o alergia a bevacizumab o sus compontes
11. Embarazo

E.5 End points

E.5.1

Primary end point(s)

1. Crude mortality at 28 days.

1. Mortalidad cruda a los 28 días.

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days after the inclusion of the patient.

A los 28 días tras la inclusión del paciente.

E.5.2

Secondary end point(s)

1. PaO2 / FiO2 ratio: it will be measured the average of three evaluations of this ratio with a time interval of at least 6 hours, before and after administration of bevacizumab at 24 hours, at 72 hours, at 7 days, 14 days and 28 days.

2. Time to clinical improvement: time (in days) to improvement in the National Early Warning Score 2 (NEWS). It is defined as time in days from randomization to any of the following criteria: (i) improvement of two points on the 7-category scale or, (ii) discharge from the hospital. The criteria reached before are used.

3. Time (in days) until improvement in oxygenation for at least 48 hours:
- Time to verify an increase in the SpO2 / FiO2 ratio with respect to the worst SpO2 / FiO2 prior to treatment with bevacizumab.
- Time until the need for oxygen to maintain saturation in ambient air ≥ 93%.
- Favorable radiological evolution established by three radiologists.
- Number of days in need of supplemental oxygen.
- Average time in the duration of:
- High flow nasal oxygen.
- Noninvasive mechanical ventilation.
- Invasive mechanical ventilation.
4. Proportion of patients requiring invasive mechanical ventilation.

Security Variables
1. Incidence of adverse events related to medication and its administration.
2. Incidence in the appearance of serious bacterial, fungal or opportunistic infections.
3. Incidence of perforation of the gastrointestinal tract.
4. Mean white blood cell and neutrophil count.
5. Average hemoglobin levels.
6. Average platelet count.
7. Average levels of creatinemia.
8. Average bilirubin levels.
9. Average ALT and AST levels.
10. Development of HTA.
11. Hemorrhages.
12. Thromboembolic events.

1. Relación PaO2/FiO2: se tendrá en cuenta el promedio de tres evaluaciones de dicho ratio con intervalo temporal de al menos 6 horas, previo y tras la administración de bevacizumab a las 24 horas, a las 72 horas, a los 7 días, 14 días y 28 días.

2. Tiempo hasta la mejoría clínica: tiempo (en días) hasta la mejoría en el National Early Warning Score 2 (NEWS). Se define como tiempo en días desde la aleatorización a cualquiera de los siguientes criterios: (i) mejoría de dos puntos en la escala de 7 categorías o, (ii) alta del hospital. Se utiliza el criterio que se alcance antes.

3. Tiempo (en días) hasta la mejoría en oxigenación durante al menos 48 horas:
- Tiempo hasta constatar un incremento en la relación SpO2/FiO2 con respecto a la peor SpO2 / FiO2 previo al tratamiento con bevacizumab.
- Tiempo hasta la ausencia de necesidad de oxígeno para mantener una saturación a aire ambiente ≥ 93%.
- Evolución radiológica favorable establecida por tres radiólogos.
- Número de días con necesidad de oxigeno suplementario.
- Tiempo medio en la duración de:
- Oxígeno nasal de alto flujo.
- Ventilación mecánica no invasiva.
- Ventilación mecánica invasiva.
4. Proporción de pacientes que precisan ventilación mecánica invasiva.

Variables de Seguridad
1. Incidencia de eventos adversos relacionados con la medicación y su administración.
2. Incidencia en la aparición de infecciones graves bacterianas, fúngicas u oportunistas.
3. Incidencia de perforación del tracto gastrointestinal.
4. Media de recuento de leucocitos y neutrófilos.
5. Media de niveles de hemoglobina.
6. Media de recuento de plaquetas.
7. Niveles medios de creatinemia.
8. Niveles medios de bilirrubina.
9. Niveles medios de ALT y AST.
10. Desarrollo de HTA.
11. Hemorragias.
12. Eventos tromboembólicos.

E.5.2.1

Timepoint(s) of evaluation of this end point

At 24 hours, at 72 hours, at 7 days, 14 days and 28 days after the inclusion of the patient.

A las 24 horas, a las 72 horas, a los 7 días, 14 días y 28 días tras la inclusión del paciente.

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

E.8.1.1

Randomised

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

Yes

E.8.1.7.1

Other trial design description

Estudio piloto

Pilot study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

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

The last visit of the last subject undergoing the trial

Última visita del último paciente del estudio.

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

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

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)

The subject will receive the best available treatment.

El paciente recibirá el mejor tratamiento disponible.

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

2020-04-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-23

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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IMP with orphan designation in the indication
Orphan Designation Number:
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