Clinical Trials Register

Summary
EudraCT Number:	2020-002123-11
Sponsor's Protocol Code Number:	HUIS-04-2020
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-05-08
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

2020-002123-11

A.3

Full title of the trial

EFFICACY OF CYCLOSPORINE IN THE TREATMENT OF COVID-19 PNEUMONIA: A RANDOMIZED CONTROLLED TRIAL.

EFICACIA DE LA CICLOSPORINA EN EL TRATAMIENTO DE LA NEUMONÍA COVID-19: ENSAYO CLÍNICO ALEATORIZADO Y CONTROLADO.

A.3.1

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

CLINICAL STUDY IN WHICH PATIENTS ARE RANDOMIZED TO RECEIVE CYCLOSPORINE VS. NON TREATMENT ASSOCIATED TO STANDARD OF CARE TO COMPARE THEIR EFFICACY IN THE COVID-19 PNEUMONIA.

ESTUDIO CLÍNICO EN EL QUE LOS PACIENTES SON ALEATORIZADOS A RECIBIR CICLOSPORINA VS. NO TRATAMIENTO ASOCIADO AL ESTÁNDAR DE TRATAMIENTO PARA COMPARAR SU EFICACIA EN LA LA NEUMONIA COVID-19.

A.3.2

Name or abbreviated title of the trial where available

CYCLO STUDY

ESTUDIO CYCLO

A.4.1

Sponsor's protocol code number

HUIS-04-2020

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	Tatiana Cobo Ibáñez
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	Hospital Universitario Infanta Sofía
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	Hospital Universitario Infanta Sofía
B.5.2	Functional name of contact point	Tatiana Cobo Ibañez
B.5.3	Address:
B.5.3.1	Street Address	Paseo de Europa 34
B.5.3.2	Town/ city	San Sebastián de los Reyes, Madrid
B.5.3.3	Post code	28702
B.5.3.4	Country	Spain
B.5.4	Telephone number	34911914037
B.5.6	E-mail	mtatiana.cobo@salud.madrid.org
B.Sponsor: 2
B.1.1	Name of Sponsor	Gemma María Mora Ortega
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	Hospital Universitario Infanta Sofía
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	Hospital Universitario Infanta Sofía
B.5.2	Functional name of contact point	Gemma María Mora Ortega
B.5.3	Address:
B.5.3.1	Street Address	Paseo de Europa 34
B.5.3.2	Town/ city	San Sebastian de los Reyes, Madrid
B.5.3.3	Post code	28702
B.5.3.4	Country	Spain
B.5.4	Telephone number	34911914061
B.5.6	E-mail	gemma.moraor@salud.madrid.org
B.Sponsor: 3
B.1.1	Name of Sponsor	Gonzalo Serralta San Martín
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	Hospital Universitario Infanta Sofía
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	Hospital Universitario Infanta Sofía
B.5.2	Functional name of contact point	Gonzalo Serralta San Martín
B.5.3	Address:
B.5.3.1	Street Address	Paseo de Europa 34
B.5.3.2	Town/ city	San Sebastian de los Reyes, Madrid
B.5.3.3	Post code	28702
B.5.3.4	Country	Spain
B.5.4	Telephone number	34911914133
B.5.6	E-mail	gonzalo.serralta@salud.madrid.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	Sandimmun Neoral 25 mg cápsulas blandas Sandimmun Neoral 50 mg cápsulas blandas Sandimun Neoral 100 mg cápsulas blandas
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farmacéutica, 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	CICLOSPORIN
D.3.9.1	CAS number	59865-13-3
D.3.9.4	EV Substance Code	SUB06250MIG
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	25 to 100
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 PNEUMONIA

NEUMONIA COVID-19

E.1.1.1

Medical condition in easily understood language

COVID-19 PNEUMONIA

NEUMONIA 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	23.1
E.1.2	Level	LLT
E.1.2	Classification code	10084383
E.1.2	Term	Novel COVID-19-infected pneumonia
E.1.2	System Organ Class	100000004862

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 efficacy of cyclosporine A (treatment group) versus non treatment (control group) in patients with acute COVID-19 pneumonia .

Evaluar la eficacia de la ciclosporina A (grupo tratamiento) frente a no tratamiento (grupo control) en pacientes con neumonía aguda COVID-19.

E.2.2

Secondary objectives of the trial

Objective 1: To estimate the lack of response 3 months after the diagnosis of COVID-19 pneumonia, differentiating whether it is due to death or development of diffuse interstitial lung disease (ILD).
Objective 2: To assess the need for pharmacological rescue and invasive mechanical ventilation with orotracheal intubation 3 months after the diagnosis of COVID-19 pneumonia.
Objectives 3: To evaluate the safety of the therapeutic strategies of interest 3 months after the diagnosis of COVID-19 pneumonia.

Objetivo 1: Estimar la falta de respuesta a los 3 meses del diagnóstico de neumonía COVID-19, diferenciando si es por fallecimiento o por desarrollo de enfermedad pulmonar intersticial difusa (EPID).
Objetivo 2: Evaluar la necesidad de tratamiento de rescate farmacológico y de ventilación mecánica invasiva con intubación orotraqueal a los 3 meses del diagnóstico de neumonía COVID-19.
Objetivos 3: Evaluar la seguridad de las estrategias terapéuticas de interés a los 3 meses del diagnóstico de neumonía COVID-19.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Adult ≥ 18 years and <80 years.
- Very characteristic initial symptoms of SARS-CoV2 infection (fever and / or cough and / or dyspnea and / or myalgia and / or asthenia and / or diarrhea) ≤ 7 days in duration.
- Presence of alveolar-interstitial lung infiltrates.
- Basal oxygen saturation <95%.
- Hospitalization.
- Patient status ≥ 3 according to the WHO clinical improvement ordinal scale.
- Positivity for the SAR-CoV2 PCR of nasal and pharyngeal exudate.

- Adulto ≥ 18 años y < 80 años.
- Clínica inicial muy característica de infección por SARS-CoV2 (fiebre y/o tos y/o disnea y/o mialgia y/o astenia y/o diarrea) ≤ 7 días de duración.
- Presencia de infiltrados pulmonares alveolo-intersticial.
- Saturación de oxígeno basal.
- Ingreso Hospitalario.
- Estado del paciente ≥ 3 según la escala ordinal de mejoría clínica de la OMS.
- Positividad para la PCR de SAR-CoV2 de exudado nasal y faríngeo.

E.4

Principal exclusion criteria

- Contraindication for the prescription of any of the study treatments.
- Inability to sign informed consent.
- Patient diagnosed with ILD.
- Allergy or intolerance to the active substance or the excipients.
- That the patient already participates in studies with other investigational treatments for COVID-19.
- Regular treatment with oral corticosteroids for disease other than COVID-19 at a dose of prednisone> 10 mg / day or equivalent.
- Treatment in the previous 30 days with IL1 or IL6 inhibitors.
- Treatment in the previous 2 months with intravenous immunoglobulins.
- Treatment in the previous 2 months with other biological therapies other than rituximab and the Il1 or Il6 inhibitors.
- Treatment in the previous 6 months with rituximab.
- Kidney failure with estimated GFR <30ml / min
- HTA of difficult control (TA> 180/100 despite adequate pharmacological treatment).
- Evidence of an intercurrent active bacterial, tuberculous, or fungal process.
- AST / ALT values greater than 5 times the upper limit of normality
- Neutrophils <500 cells / mm3 or Platelets <50,000 cells / mm3.
- Active neoplasms.
- Pregnancy and lactation.
- Significant comorbidity (CIRS scale> 29).

- Contraindicación para la prescripción de alguno de los tratamientos del estudio.
- Incapacidad de otorgar consentimiento informado.
- Estar diagnosticado de EPID.
- Alergia o intolerancia al principio activo o los excipientes.
- Que el paciente ya participe en estudios con otros tratamientos en investigación para el COVID-19.
- Tratamiento habitual con corticoides orales por enfermedad diferente a COVID-19 a una dosis de prednisona >10 mg/día o equivalente.
- Tratamiento en los 30 días previos con inhibidores de IL1 o de IL6.
- Tratamiento en los 2 meses previos con inmunoglobulinas intravenosas.
- Tratamiento en los 2 meses previos con otras terapias biológicas diferentes a rituximab y a los inhibidores de Il1 o Il6.
- Tratamiento en los 6 meses previos con rituximab.
- Insuficiencia renal con FG estimado < 30ml/min
- HTA de difícil control (TA > 180/100 a pesar de tratamiento farmacológico adecuado).
- Evidencia de proceso infeccioso bacteriano, tuberculoso, o fúngico activo intercurrente.
- Valores de AST/ALT superiores a 5 veces el límite superior de la normalidad
- Neutrófilos < 500 células/mm3 o Plaquetas < 50.000 células/mm3.
- Neoplasias activas.
- Embarazo y lactancia.
- Comorbilidad importante (Escala CIRS >29).

E.5 End points

E.5.1

Primary end point(s)

Rate of patients achieving complete response 3 months after being diagnosed of COVID-19 pneumonia.

Tasa de pacientes que alcanzan respuesta completa a los 3 meses del diagnóstico de neumonía COVID-19.

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months

3 meses

E.5.2

Secondary end point(s)

1. Rate of patients achieving partial response 3 months after diagnosis of COVID-19 pneumonia.
2. Rate of patients who do not reach a response 3 months after the diagnosis of COVID-19 pneumonia, differentiating whether it is due to death or due to the development of ILD.
3. Rate of patients receiving invasive mechanical ventilation (IMV) with orotracheal intubation (IOT) 3 months after the diagnosis of COVID-19 pneumonia.
4. Rate of patients requiring rescue treatment with methylprednisolone or biological therapy 3 months after the diagnosis of COVID-19 pneumonia.
5. Time elapsed from diagnosis to response, receiving IMV with IOT, and requiring rescue treatment with methylprednisolone or biological therapy.
6. Frequency and incidence of adverse events after 3 months of being diagnosed of COVID-19 pneumonia.

1. Tasa de pacientes que alcanzan respuesta parcial a los 3 meses del diagnóstico de neumonía COVID-19.
2. Tasa de pacientes que no alcanzan respuesta a los 3 meses del diagnóstico de neumonía COVID-19, diferenciando si es por fallecimiento o por desarrollo de EPID.
3. Tasa de pacientes que reciben ventilación mecánica invasiva (VMI) con intubación orotraqueal (IOT) a los 3 meses del diagnóstico de neumonía COVID-19.
4. Tasa de pacientes que requieren tratamiento de rescate con metilprednisolona o terapia biológica los 3 meses del diagnóstico de neumonía COVID-19.
5. Tiempo trascurrido desde el diagnóstico hasta alcanzar respuesta, recibir VMI con IOT, y requerir tratamiento de rescate con metilprednisolona o terapia biológica.
6. Frecuencia e incidencia de acontecimientos adversos a los 3 meses del diagnóstico de neumonía COVID-19.

E.5.2.1

Timepoint(s) of evaluation of this end point

3 months

3 meses

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)

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

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

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

LVLS

La última visita del ultimo sujeto incluido en el ensayo.

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:

118

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