Clinical Trials Register

Summary
EudraCT Number:	2020-001445-39
Sponsor's Protocol Code Number:	TACRO-BELL-COVID
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:	2020-04-03
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

Spain - AEMPS

A.2

EudraCT number

2020-001445-39

A.3

Full title of the trial

PRAGMATIC, CONTROLLED, OPEN, SINGLE CENTER, RANDOMIZED, PHASE II CLINICAL TRIAL TO EVALUATE METHYLPREDNISOLONE PULSES AND TACROLIMUS IN HOSPITALIZED PATIENTS WITH SEVERE PNEUMONIA SECONDARY TO COVID-19 (TACROVID)

ENSAYO CLÍNICO DE FASE II, PRAGMÁTICO, CON ASIGNACIÓN ALEATORIA, CONTROLADO, ABIERTO Y UNICÉNTRICO PARA EVALUAR PULSOS DE METILPREDNISOLONA Y TACROLIMUS EN PACIENTES HOSPITALIZADOS CON NEUMONIA GRAVE SECUNDARIA A COVID-19 (TACROVID)

A.3.1

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

CLINICAL TRIAL TO EVALUATE METHYLPREDNISOLONE PULSES AND TACROLIMUS IN HOSPITALIZED PATIENTS WITH SEVERE PNEUMONIA SECONDARY TO COVID-19 (TACROVID)

ENSAYO CLÍNICO PARA EVALUAR PULSOS DE METILPREDNISOLONA Y TACROLIMUS EN PACIENTES HOSPITALIZADOS CON NEUMONIA GRAVE SECUNDARIA A COVID-19 (TACROVID)

A.4.1

Sponsor's protocol code number

TACRO-BELL-COVID

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	Dr. Xavier Solanich Moreno. Servei Medicina Interna. Hospital de Bellvitge
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	pending
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	Dr. Xavier Solanich Moreno. Servei Medicina Interna. Hospital de Bellvitge
B.5.2	Functional name of contact point	Xavier Solanich Moreno
B.5.3	Address:
B.5.3.1	Street Address	Feixa Llarga
B.5.3.2	Town/ city	L'Hospitalet de Llobregat
B.5.3.3	Post code	08907
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034932602324
B.5.5	Fax number	0034932607967
B.5.6	E-mail	xsolanich@bellvitgehospital.cat

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.2.1.2	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.3.1	Product name	Metilprednisolona
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METHYLPREDNISOLONE
D.3.9.3	Other descriptive name	METHYLPREDNISOLONE
D.3.9.4	EV Substance Code	SUB08872MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 125
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	Modigraf
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma Europe B.V.
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	Powder for oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TACROLIMUS
D.3.9.1	CAS number	104987-11-3
D.3.9.4	EV Substance Code	SUB10797MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.1 to 0.2
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

Hospitalized patients with severe pneumonia secondary to COVID-19.

Pacientes hospitalizados con neumonía grave secundaria a COVID-19

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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10051905
E.1.2	Term	Coronavirus infection
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10070255
E.1.2	Term	Coronavirus test positive
E.1.2	System Organ Class	10022891 - Investigations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Main objective:
- To study the time (days) to reach clinical stability after randomization in hospitalized patients with severe pneumonia secondary to COVID-19, and elevated inflammatory parameters.

Objetivo principal:
- Estudiar el tiempo (días) hasta alcanzar la estabilidad clínica tras iniciar la aleatorización en pacientes hospitalizados con neumonía grave secundaria a COVID-19, y elevación de parámetros inflamatorios.

E.2.2

Secondary objectives of the trial

Clinical
-time to reach an afebrile state during 48 hours.
-time to reach PaO2/FiO2 >400 and/or SatO2/FiO2 >400
-time until you reach a FR ≤ 24 rpm for 48 hours
-time to D-dimer normalization (<250 ug/L)
-time until PCR is normalized (<5mg/L).
-time to normalisation of ferritin (<400ug/L).
-impact of immunosuppressive treatment on viral dynamics using quantitative PCR.
-duration of treatment with tacrolimus.
-duration of the inpatient stay.
-Percentage of patients requiring artificial respiratory support
-duration of artificial respiratory support needs to be maintained.
-mortality Incidence COVID at 28 and 56 days
-mortality incidence all-cause at 28 and 56 days
-relapses of COVID-19 pneumonia at 28 and 56 days
-Analysis of expanded cytokine profile (day 0 and every 7 days)
Safety
-side effects according to the severity attributed to tacrolimus during its administration.
-side effects according to the severity attributed to other treatments administered

Clínicos
-tiempo hasta alcanzar un estado afebril durante 48 horas.
-tiempo hasta alcanzar PaO2/FiO2 >400 y/o SatO2/FiO2 >400
-tiempo hasta alcanzar FR ≤ 24 rpm: 48 horas.
-tiempo hasta la normalización de dímero D (<250 ug/L)
-tiempo hasta la normalización PCR (<5mg/L).
-tiempo hasta la normalización de la ferritina (<400ug/L).
-impacto del tratamiento inmunosupresor en la dinámica viral mediante PCR cuantitativa.
-duración del tto con tacrolimus.
-duración estancia hospitalaria.
-Porcentaje de pacientes que requieren dispositivos de soporte ventilatorio
-duración que es necesario mantener soporte ventilatorio.
-mortalidad por COVID-19 a los 28 y 56 días
-mortalidad por cualquier causa a los 28 y 56
- recaídas de neumonía por COVID-19 a los 28 y 56 días
- Analizar el perfil de citocinas ampliado dia 0 y cada 7 días
Seguridad:
-efectos secundarios según la gravedad atribuida a tacrolimus
efectos secundarios según la gravedad atribuid a otros tratamientos

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria:

Patients admitted to the HUB with COVID-19 infection confirmed by fluorescent RT-PCR who meet all of the following criteria:
1 New-onset radiological infiltrates (either by plain chest radiography, computed tomography or chest ultrasound) attributed to COVID-19,
2. Respiratory failure (PaO2/FiO2 < 300 or satO2/FiO2 < 220) attributed to 1,
3.PCR > 100 mg/L and/or D-Dimer > 1000 μg/L and/or Ferritin > 1000 ug/L attributed to 1,
4. Age ≥ 18 years.
5. The subject, his legal representative or closest relative (in case of the subject's incapacity due to the seriousness of the clinical situation) that gives informed consent

Criterios de inclusión:

Pacientes ingresados en el HUB con infección por COVID-19 confirmada mediante fluorescent RT-PCR i que cumplan todos los criterios siguientes:
1- Infiltrados radiológicos de nueva aparición (bien por radiografía simple de tórax, tomografía axial computarizada o ecografía de tórax) atribuidos a COVID-19,
2- Insuficiencia respiratoria (PaO2/FiO2 < 300 o satO2/FiO2 < 220) atribuida a 1,
3- PCR > 100 mg/L y/o D-Dimero > 1000 μg/L y/o Ferritina > 1000 ug/L atribuida a 1,
4- Edad ≥ 18 años.
5- El sujeto, su representante legal o familiar más cercano (en caso de incapacidad del sujeto por gravedad de la situación clínica) otorgan el consentimiento informado

E.4

Principal exclusion criteria

Exclusion criteria:
1. Imminent death (life expectancy ≤ 24h).
2. Contraindication for the use of tacrolimus according to the summary of product charactheristics .
3. Known adverse reactions to treatment
4. Have participated in a clinical trial in the last 3 months.

Criterios de exclusión:
1. Muerte inminente (expectativa de vida ≤ a 24h).
2. Contraindicación para el uso de tacrolimus según la ficha técnica del producto.
3. Reacciones adversas conocidas al tratamiento
4. Haber participado en un ensayo clínico los últimos 3 meses.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint (for the main objective of effectiveness):
- Time (days) to clinical stability after initiation of trial treatment in hospitalised patients with severe pneumonia secondary to COVID-19 and elevated inflammatory parameters

Criterio principal (para el objetivo principal de eficacia):
- Tiempo (días) hasta alcanzar la estabilidad clínica después de iniciar el tratamiento del ensayo, en pacientes hospitalizados con neumonía grave secundaria a COVID-19 y parámetros inflamatorios elevados.

E.5.1.1

Timepoint(s) of evaluation of this end point

Throughout the study until clinical stability

Durante todo el estudio hasta alcanzar la estabilidad clínica

E.5.2

Secondary end point(s)

Secondary endpoints (for secondary objectives):

Clinical and analytical:
- Time ('days') to reach an afebrile state for 48 hours
- Time ('days') to PaO2/FiO2 >400 and/or SatO2/FiO2 >400 for 48 hours.
- Time ('days') to reach a FR ≤ 24 rpm for 48 hours
- Time ('days') until normalization of D-dimer (<250 ug/L),
- Time ('days') until IL-6 normalization (<5mg/L).
- Time ('days') to Ferritin normalization (<400ug/L)
- Change (percentage) in the viral load (PCR) before the start of the drug from day 7.
- Number of patients requiring non-invasive artificial respiratory support devices (NIV, FNG, etc.)
- Number of patients requiring invasive artificial respiratory support devices (VM)
- Time ('days') in intensive care unit.
- Time ('days') in semi-intensive care unit.
- Number of days of inpatient stay (from the day of treatment inititation to discharge from hospital)
- Number of days with the trial treatment.
- Quantify the cytokines studied in the expanded cytokine profile before the start of treatment and after 7 days of trial treatment.
- Long-term efficacy (at 28 and 56 days after trial treatment initiation) will be assessed by measuring whether clinical stability is maintained and the incidence of relapses of COVID-19 peumonia.

Safety:
- Incidence of adverse events according to their severity and relationship to clinical trial treatment.
- Incidence of adverse events according to their severity for other reasons than clinical trial treatment

Mortality:
- Incidence of mortality due to COVID-19 at 28 and 56 days after the beginning of the clinical trial treatment.
- Incidence of all-cause mortality at 28 and 56 days after starting clinical trial treatment.

Criterios secundarios (para los objetivos secundarios):

Clínicos y analíticos:
- Tiempo (‘días’) hasta alcanzar un estado afebril durante 48 horas.
- Tiempo (‘días’) hasta alcanzar una PaO2/FiO2 >400 y/o SatO2/FiO2 >400 durante 48 horas.
- Tiempo (‘días’) hasta alcanzar una FR ≤ 24 rpm durante 48 horas
- Tiempo (‘días’) hasta la normalización del dímero D (<250 ug/L),
- Tiempo (‘días’) hasta la normalización de IL-6 (<5mg/L).
- Tiempo (‘días’) hasta la normalización de Ferritina (<400ug/L)
- Cambio (porcentaje) de la cantidad viral (PCR) antes del inicio del fármaco respecto al día 7.
- Número de pacientes que requiere dispositivos de soporte ventilatorio no invasivo (VMNI, GNAF…)
- Número de pacientes que requiere dispositivos de soporte ventilatorio invasivo (VM)
- Tiempo (‘días’) en unidad de cuidados intensivos.
- Tiempo (‘días’) en unidad de cuidados semi-intensivos.
- Número de días de estancia hospitalaria (desde el día del inicio del tratamiento del ensayo hasta el alta hospitalaria)
- Número de días con el tratamiento del ensayo.
- Cuantificar las citocinas estudiadas en el perfil de citocinas ampliado antes del inicio del tratamiento y tras 7 días del tratamiento del ensayo.
- Eficacia a largo plazo (a los 28 y 56 días del inicio del tratamiento del ensayo) se evaluara midiendo si se mantiene la estabilidad clínica y la incidencia de recaídas de neumonía por COVID-19.

Seguridad:
- Incidencia de acontecimientos adversos según su gravedad y relación con el tratamiento del ensayo.
- Incidencia de acontecimientos adversos según su gravedad por motivos diferentes al tratamiento del ensayo.

Mortalidad:
- Incidencia de mortalidad por COVID-19 a los 28 y 56 días del inicio del tratamiento del ensayo.
- Incidencia de mortalidad por cualquier causa a los 28 y 56 días del inicio del tratamiento del ensayo.

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout the study

Durante todo el estudio

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

tratamiento estándar antiviral

antiviral standard treatment

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

The study will end when the evaluation of the last patient included in
the study
"Last visit last patient"

El estudio finalizará cuando finalice la evaluación del último paciente incluido en
el estudio
"Last Patient-Last Visit"

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

Yes

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

In case of the subject's incapacity due to the seriousness of the clinical situation
(his legal representative or closest relative that gives informed consent )

Incapacidad del sujeto por gravedad de la situación clínica ( su representante legal o familiar más cercano otorgan el consentimiento informado)

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)

Patients who complete their participation in this study will continue with the medical tests and treatments prescribed by their doctor according to their usual practice.

Los pacientes que finalicen su participación en este estudio, continuarán con las pruebas médicas y tratamientos que les prescriba
su médico de acuerdo a su práctica clínica habitual.

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

2020-03-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-26

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-06-29

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