Clinical Trials Register

Summary
EudraCT Number:	2020-001717-20
Sponsor's Protocol Code Number:	COVIDIOL
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

2020-001717-20

A.3

Full title of the trial

Prevention and treatment with Calcifediol of Coronavirus COVID-19-induced acute respiratory syndrome (SARS)

Prevención y tratamiento con Calcifediol del síndrome respiratorio agudo (SARS) inducido por Coronavirus COVID-19

A.3.1

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

Prevention and treatment with Calcifediol of respiratory problems caused by COVID-19

Prevención y tratamiento con Calcifediol de problemas respiratorios causados por COVID-19

A.4.1

Sponsor's protocol code number

COVIDIOL

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	Hidroferol 0,266 mg cápsulas blandas
D.2.1.1.2	Name of the Marketing Authorisation holder	FAES FARMA 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	Capsule, soft
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	CALCIFEDIOL
D.3.9.1	CAS number	19356-17-3
D.3.9.4	EV Substance Code	SUB06045MIG
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	0.266
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

Severe Acute Respiratory Syndrome in subjects with COVID-19

Síndrome respiratorio agudo severo en pacientes con COVID-19

E.1.1.1

Medical condition in easily understood language

Severe lung problems in patients with COVID-19

Problemas pulmonares severos 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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10061986
E.1.2	Term	SARS
E.1.2	System Organ Class	10021881 - Infections and infestations

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 demonstrate that in patients ≥18 and <90 years, positive for coronavirus, newly hospitalized with or without oxygen respiratory support, conventional or non-invasive ventilation (BIPAP type), treatment with Calcifediol will decrease the need for ventilation invasive and admissions to the Intensive Care Unit and deaths

Demostrar que en pacientes ≥18 y <90 años, positivos para coronavirus, recién hospitalizados con o sin soporte respiratorio oxígeno, convencional o ventilación no invasiva (tipo BIPAP) el tratamiento con Calcifediol disminuirá la necesidad de ventilación invasiva e ingresos en la Unidad de Cuidados Intensivos y fallecimientos

E.2.2

Secondary objectives of the trial

- To assess if the treatment in newly hospitalized patients with non-invasive ventilation will decrease the time at discharge
- To evaluate in patients who require invasive ventilation and ICU admission during the process, if the treatment will decrease the number of days until the withdrawal of invasive ventilation and if it will decrease the time (in days) upon discharge from the ICU
- To assess if the treatment improves the clinical evolution
- To evaluate if the treatment improves the evolution of hematimetry & biochemistry parameters
- To assess if the treatment decreases the markers of inflammation
- To confirm that low serum 25OHD levels have a role in the negative evolution of patients to SARS
- To evaluate improvement in the O2/FiO2 Saturation ratio, improvement in the degree of dyspnea according to the Borg analog scale, improvement of radiological findings by simple radiology, improvement in transcutaneous O2 saturation and potential side effects of treatment

- Evaluar si el tratamiento en pacientes recién hospitalizados con ventilación no invasiva disminuirá el tiempo al alta
- Evaluar en pacientes que requieren ventilación invasiva y admisión en la UCI durante el proceso, si el tratamiento disminuirá el número de días hasta la retirada de la ventilación invasiva y si disminuirá el tiempo (en días) al alta de UCI
- Evaluar si el tratamiento mejora la evolución clínica
- Evaluar si el tratamiento mejora la evolución de los parámetros de hematimetría y bioquímica.
- Evaluar si el tratamiento disminuye los marcadores de inflamación
- Para confirmar que los niveles bajos de 25OHD en suero tienen un papel en la evolución negativa de los pacientes al SRAS
- Evaluar la mejora en la relación de saturación de O2 / FiO2, la mejora en el grado de disnea según la escala analógica de Borg, la mejora de los hallazgos radiológicos por radiología simple, la mejora en la saturación transcutánea de O2 y los posibles efectos secundarios del tratamiento

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

In 50 patients (25 randomized from each group), aliquots of 2 cc of blood will be collected on days 0, 3, 7, 14, 21 and 28 days for quantification of:
to. Disease-related inflammation markers IL 1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, IL118, 1L32, tumor necrosis factor (TNF) α, interferon-γ , macrophage granulocyte colony-stimulating factor- (GM-CSF) and chemokines: CCL2, CCL3, CCL5, CXCL8, CXCL9
b. Metabolites of Vitamin D (25 OHD, 1,25 (OH) D and 24,25 (OH) 2D3 ratio of 25OHD / 24,25 (OH) 2D, [system catabolism marker]
c. Viral load evolution, if available, will be studied in Córdoba.

En 50 pacientes (25 aleatorizados de cada grupo) se recogerán en días 0, 3, 7, 14,21 y 28 días 3 alícuotas de 2 cc de sangre para cuantificación de:
a. Marcadores de inflamación relacionados con la enfermedad IL 1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, IL118, 1L32, factor de necrosis tumoral (TNF) α, interferón-γ, factor estimulante colonia de granulocitos macrófagos- (GM-CSF) y chemoquinas: CCL2, CCL3, CCL5, CXCL8, CXCL9
b. Metabolitos de Vitamina D (25 OHD, 1,25(OH)D y 24,25 (OH)2D3 ratio de 25OHD/24,25(OH)2D, [marcador de catabolismo del sistema]
c. En Córdoba se estudiará evolución de carga viral, si disponible.

E.3

Principal inclusion criteria

1. Age ≥ 18 and <90 years
2. Diagnosis confirmed by COVID-19 PCR
3. Radiological image compatible with inflammatory pleuropulmonary exudate
4. 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 inflamatorio
4. Firma de consentimiento informado directo o delegado

E.4

Principal exclusion criteria

1. Being on treatment with Calcifediol or Colecalciferol in any of its presentations and dosage
2. Intolerance or allergy to Calcifediol or its components
3. Pregnancy

1. Estar en tratamiento con Calcifediol o Colecalciferol en cualquiera de sus presentaciones y posologías
2. Intolerancia o alergia a Calcifediol o sus componentes
3. Embarazo

E.5 End points

E.5.1

Primary end point(s)

1) Admission to the Intensive Care Unit or
2) Death

1) Ingreso en Unidad de Cuidados intensivos o
2) Fallecimiento

E.5.1.1

Timepoint(s) of evaluation of this end point

Daily throughout the subject duration in the trial.

Diariamente durante toda la duración del sujeto en el estudio.

E.5.2

Secondary end point(s)

CLINICAL EVOLUTION
1) Time from the onset of symptoms to discharge of patients in conventional hospitalization.
2) In patients who in the course of evolution required admission with mechanical ventilation in the ICU:
to. Time until admission to the Intensive Care Unit
b. Time until mechanical ventilation is removed
c. ICU registration
3) Collection of clinical evolution data in all patients (“Check list of the disease”) on days 0, 3, 7, 14 and 21 and 28.

BLOOD ANALYTICS
1) Collection of hematimetry and biochemistry data (“Check list of the disease”) in all patients, including RCT and Ca / Cr analysis on days 0, 3, 7, 14, 21 and 28
2) [SUB-STUDY] 50 aliquots of 2 cc for quantification will be collected in 50 patients (25 randomized from each group) for quantification on days 0, 3, 7, 14, 21 and 28 days:
a) Disease-related inflammation markers IL 1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, IL118, 1L32, tumor necrosis factor (TNF) α, interferon -γ, macrophage granulocyte colony stimulating factor- (GMCSF) and chemokines: CCL2, CCL3, CCL5, CXCL8, CXCL9;
b) Vitamin D metabolites (25 OHD, 1,25 (OH) D and 24,25 (OH) 2D3 ratio of 25OHD / 24,25 (OH) 2D, [system catabolism marker]
c) Córdoba will study the evolution of viral load, if available.

RESPIRATORY PARAMETERS, OXYGEN THERAPY, AND RESPIRATORY SUPPORT
1) Respiratory rate and SatO2, evaluated at baseline and on days 3, 7, 14, 21 and 28
2) O2 / FiO2 saturation ratio: the average of three evaluations of said ratio will be taken into account with a time interval of at least 6 hours, before and after the administration of Calcifediol at 24 hours, at 3 days, at 7 days , at 14 days and at 28 days.
3) Evaluate degree of dyspnea at 0 3, 7, 14 days with the Borg analog scale.
4) Level of consciousness, assessed at baseline and on days 3, 7, 14, 21 and 28
5) Applied oxygen (FiO2) evaluated at baseline and on days 3, 7, 14, 21 and 28
- Time until the absence of oxygen need, at least for 48 hours to maintain a saturation at room air ≥ 93%.
- Number of days in need of supplemental oxygen.
- Average time in the duration of:
o High flow nasal oxygen
o Invasive mechanical ventilation
6) Collect patients who require invasive mechanical ventilation, at baseline and on days 3, 7, 14, 21 and 28.
7) Collect radiological evolution established by baseline radiological evaluator, day 14 and day 28
8) Collection of thromboembolic events.

Security Variables
1. Collection of adverse events potentially related to the medication and its administration.
2. Vital Signs and Physical Exploration
3. Blood biochemistry
4. Hematological parameters

EVOLUCIÓN CLÍNICA
1) Tiempo desde el inicio de síntomas hasta Alta de pacientes en Hospitalización convencional.
2) En pacientes que en el curso de la evolución precisaron ingreso con ventilación mecánica en UCI:
a. Tiempo hasta ingreso en Unidad de Cuidados intensivos
b. Tiempo hasta retirada ventilación mecánica
c. Alta en UCI
3) Recogida en todos los pacientes datos evolución clínica (“Check list de la enfermedad”) los días 0, 3, 7, 14 y 21 y 28.

ANALÍTICA SANGUÍNEA
1) Recogida en todos los pacientes datos de hematimetría y bioquímica (“Check list de la enfermedad”) incluyendo análisis de ECA y Ca/Cr los días 0, 3, 7, 14,21 y 28
2) [SUBESTUDIO] Se recogerán en 50 pacientes (25 aleatorizados de cada grupo) para cuantificación los días 0, 3, 7, 14,21 y 28 días 3 alícuotas de 2 cc para cuantificación:
a) Marcadores de inflamación relacionados con la enfermedad IL 1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12, IL118, 1L32, factor de necrosis tumoral (TNF) α, interferón-γ, factor estimulante colonia de granulocitos macrófagos- (GMCSF) y chemoquinas: CCL2, CCL3, CCL5, CXCL8, CXCL9;
b) Metabolitos de Vitamina D (25 OHD, 1,25(OH)D y 24,25 (OH)2D3 ratio de 25OHD/24,25(OH)2D, [marcador de catabolismo del sistema]
c) en Córdoba se estudiará evolución de carga viral, si disponible.

PARÁMETROS RESPIRATORIOS, OXIGENOTERAPIA, Y SOPORTE RESPIRATORIO
1) Frecuencia respiratoria y SatO2, evaluado basal y los días 3, 7, 14, 21 y 28
2) Relación saturación O2/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 Calcifediol a las 24 horas, a los 3 días, a los 7 días, a los 14 días y a los 28 días.
3) Evaluar grado de disnea a los 0 3, 7, 14 días con la escala analógica de Borg.
4) Nivel de conciencia, evaluado basal y los días 3, 7, 14, 21 y 28
5) Oxigeno aplicado (FiO2) evaluado basal y los días 3, 7, 14, 21 y 28
- Tiempo hasta la ausencia de necesidad de oxígeno, al menos durante 48 horas para mantener una saturación a aire ambiente ≥ 93%.
- Número de días con necesidad de oxigeno suplementario.
- Tiempo medio en la duración de:
o Oxigeno nasal de alto flujo
o Ventilación mecánica invasiva
6) Recoger pacientes que precisan ventilación mecánica invasiva, basal y los días 3, 7, 14, 21 y 28.
7) Recoger evolución radiológica establecida por evaluador radiológico basal, día 14 y día 28
8) Recogida de eventos tromboembólicos.

Variables de Seguridad
1. Recogida de eventos adversos potencialmente relacionados con la medicación y su administración.
2. Signos Vitales y Exploración Física
3. Bioquímica sanguínea
4. Parámetros hematológicos

E.5.2.1

Timepoint(s) of evaluation of this end point

Days 0, 3, 7, 14, 21 and 28

Días 0, 3, 7, 14, 21 y 28

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

Mejor terapia disponible

Best available 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

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

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

The last visit of the last subject undergoing the trial.

Última visita del último paciente.

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:

308

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

700

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

Yes

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

1008

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)

Best available treatment.

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

2020-04-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-16

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

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IMP with orphan designation in the indication
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