Clinical Trials Register

Summary
EudraCT Number:	2020-001662-11
Sponsor's Protocol Code Number:	CINC424J12301
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-05-08
Trial results	View 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

2020-001662-11

A.3

Full title of the trial

Phase 3 randomized, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety of ruxolitinib in patients with COVID-19 associated cytokine storm (RUXCOVID)

Estudio de fase 3, multicéntrico, aleatorizado, doble ciego y controlado con placebo para evaluar la eficacia y seguridad de ruxolitinib en pacientes con síndrome de liberación de citoquinas asociado a COVID-19 (RUXCOVID)

A.3.1

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

Phase 3 randomized, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety of ruxolitinib in patients with COVID-19 associated cytokine storm (RUXCOVID)

A.3.2

Name or abbreviated title of the trial where available

RUXCOVID

A.4.1

Sponsor's protocol code number

CINC424J12301

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	Novartis Farmacéutica, S.A.
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmacéutica S.A.
B.5.2	Functional name of contact point	Trial Monitoring Organization (TMo)
B.5.3	Address:
B.5.3.1	Street Address	Gran Vía de les Corts Catalanes 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	34 90 0353036
B.5.5	Fax number	34 93 2479903
B.5.6	E-mail	eecc.novartis@novartis.com

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	Jakavi
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	ruxolitinib
D.3.2	Product code	INC424
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	ruxolitinib
D.3.9.1	CAS number	1092939-17-7
D.3.9.2	Current sponsor code	INC424
D.3.9.3	Other descriptive name	RUXOLITINIB PHOSPHATE
D.3.9.4	EV Substance Code	SUB32897
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	5
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

COVID-19 associated cytokine storm

Síndrome de liberación de citoquinas asociado a COVID-19.

E.1.1.1

Medical condition in easily understood language

COVID-19

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

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 evaluate the efficacy (as measured by a composite endpoint of proportion of patients who die, develop respiratory failure [require mechanical ventilation], or require intensive care unit [ICU] care) of ruxolitinib + standard-of-care (SoC) therapy compared with placebo + SoC therapy, for the treatment of COVID-19 by Day 29

Evaluar la eficacia (según una variable compuesta por proporción de pacientes que mueren, desarrollan fallo respiratorio [requieren ventilación mecánica] o requieren ingreso en la unidad de cuidados intensivos [UCI]) de ruxolitinib + tratamiento de referencia (SoC), en comparación con placebo + SoC, para el tratamiento de COVID-19 el día 29.

E.2.2

Secondary objectives of the trial

evaluate efficacy (as measured by clinical status using a 9-point ordinal scale) of ruxolitinib + SoC therapy compared with placebo + SoC therapy, for treatment of COVID-19.
evaluate efficacy of ruxolitinib + standard-of-care (SoC) therapy compared with placebo + SoC therapy, on in-hospital outcomes in patients with COVID-19.
evaluate efficacy of ruxolitinib + SoC therapy, compared with placebo + SoC therapy, in change in the National Early Warning Score (NEWS2) score in patients with COVID-19.
evaluate efficacy of ruxolitinib + SoC therapy, compared with placebo + SoC therapy, in change in SpO2/FiO2 ratio in patients with COVID-19.
evaluate efficacy of ruxolitinib + SoC therapy, compared with placebo + SoC therapy, in proportion of patients with no oxygen therapy (defined as oxygen saturation >/= 94% on room air) in patients with COVID-19.
evaluate safety of ruxolitinib + standard-of-care (SoC) therapy compared with placebo + SoC therapy, in treatment of patients with COVID-19.

Evaluar la eficacia (según el estado clínico medido por la escala ordinal de 9 puntos) de ruxolitinib + SoC en comparación con placebo + SoC, para el tratamiento de COVID-19.
Evaluar la eficacia de ruxolitinib + SoC, en comparación con placebo + SoC, en los resultados durante el ingreso hospitalario de pacientes con COVID-19.
Evaluar la eficacia de ruxolitinib + SoC, en comparación con placebo + SoC, en el cambio en la puntuación de la National Early Warning Score (NEWS2) en pacientes con COVID-19.
Evaluar la eficacia de ruxolitinib + SoC, en comparación con placebo + SoC, en el cambio en el índice SpO2/FiO2 en pacientes con COVID-19
Evaluar la eficacia de ruxolitinib + SoC, en comparación con placebo + SoC, en el porcentaje de pacientes sin oxigenoterapia (definida como saturación de oxígeno >/=94 % respirando aire ambiente) en pacientes con COVID-19
Evaluar la seguridad de ruxolitinib + SoC, en comparación con placebo + SoC, en el tratamiento de pacientes con COVID-19.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patient or guardian/health proxy must provide informed consent (and assent if applicable) before any study assessment is performed.
• Male and female patients aged >/=12 years (or >/= the lower age limit allowed by Health Authority and/or Ethics Committee/Institutional Review Board approvals).
• Patients with coronavirus (SARS-CoV-2) infection confirmed by polymerase chain reaction (PCR) test or another rapid test from the respiratory tract prior to randomization.
• Patients currently hospitalized or will be hospitalized prior to randomization.
• Patients with lung imaging showing pulmonary infiltrates (chest X-ray or CT scan) prior to randomization.
• Patients, who meet at least one of the below criteria:
•Respiratory frequency >/=30/min;
•Oxygen saturation </= 93% on room air;
•Arterial oxygen partial pressure (PaO2)/ fraction of inspired oxygen (FiO2) < 300mmHg (1mmHg=0.133kPa) (corrective formulation should be used for higher altitude regions (over 1000m).

Additional inclusion criteria as per main section in the protocol may apply.

- El paciente o tutor/persona allegada debe dar el consentimiento informado (y el asentimiento si procede) antes de que se realice cualquier evaluación del estudio.
- Pacientes de ambos sexos >/=12 años (o >/= límite inferior de edad permitido por las Autoridades Sanitarias o aprobado por el Comité de Ética de la Investigación con medicamentos).
- Pacientes con infección por coronavirus (SARS-CoV-2) confirmada por una prueba de reacción en cadena de la polimerasa (PCR) u otra prueba rápida del tracto respiratorio realizadas antes de la aleatorización.
- Pacientes actualmente hospitalizados o que serán hospitalizados antes de la aleatorización.
- Pacientes con infiltrados pulmonares anteriores a la aleatorización observados mediante técnicas de imagen (radiografía de tórax o TC)
- Pacientes que cumplan al menos uno de los siguientes criterios:
. Frecuencia respiratoria >/=30/min;
. Saturación de oxígeno </=93 % respirando aire ambiente;
. Presión parcial de oxígeno arterial (PaO2)/fracción de oxígeno inspirado (FiO2) <300 mmHg (1 mmHg = 0,133 kPa) (debe utilizarse la formulación correctiva para regiones de mayor altitud [más de 1000 m]).

Pueden aplicarse otros criterios principales de inclusión según protocolo.

E.4

Principal exclusion criteria

• History of hypersensitivity to any drugs or metabolites of similar chemical classes as ruxolitinib.
• Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL (>176.8 μmol/L), or have estimated creatinine clearance < 30 ml/min measured or calculated by Cockroft Gault equation or calculated by the updated bedside Schwartz equation.
• Suspected uncontrolled bacterial, fungal, viral, or other infection (besides COVID-19).
• Currently intubated or intubated between screening and randomization.
• In intensive care unit (ICU) at time of randomization.
• Patients who are on anti-rejection, immunosuppressant or immunomodulatory drugs (i.e. tocilizumab, ruxolitinib, canakinumab, sarilumab, anakinra).
• Unable to ingest tablets at randomization.
• Pregnant or nursing (lactating) women.

Additional exclusion criteria as per main section in the protocol may apply.

- Antecedentes de hipersensibilidad a cualquier fármaco o metabolitos de clases químicas similares a la de ruxolitinib.
- Función renal gravemente alterada definida por un valor de creatinina sérica >2 mg/dl (>176,8 μmol/l), o un aclaramiento de la creatinina estimado <30 ml/min medido o calculado por la ecuación de Cockroft-Gault o calculado por la ecuación de Schwartz bedside actualizada.
- Sospecha de infección incontrolada bacteriana, fúngica, vírica o de otro tipo (además de la infección por COVID-19).
- Intubado actualmente o entre la selección y la aleatorización.
- Estar en la unidad de cuidados intensivos (UCI) en el momento de la aleatorización.
- Pacientes que estén tomando fármacos antirrechazo, inmunosupresores o inmunomoduladores (es decir, tocilizumab, ruxolitinib, canakinumab, sarilumab y anakinra).
- Personas que no puedan ingerir comprimidos en la aleatorización.
- Mujeres embarazadas o en periodo de lactancia.

Pueden aplicarse otros criterios principales de exclusión según protocolo.

E.5 End points

E.5.1

Primary end point(s)

composite endpoint defined as proportion of patients who
- die OR
- develop respiratory failure (require mechanical ventilation) OR
- require intensive care unit (ICU) care

criterio de valoración compuesto definido como la proporción de pacientes que
- mueran
- desarrollan fallo respiratorio (requieren ventilación mecánica) o
- requieren ingreso en la unidad de cuidados intensivos (UCI)

E.5.1.1

Timepoint(s) of evaluation of this end point

29 days

29 días

E.5.2

Secondary end point(s)

1. clinical status is measured with the 9-point ordinal scale. The scoring is - Uninfected patients have a score 0 (no clinical or virological evidence of infection). - Ambulatory patients (not in hospital or in hospital and ready for discharge) can have a score 1 (no limitation of activities) or 2 (limitation of activities). - Hospitalized patients with mild disease can have score 3 (no oxygen therapy defined as SpO2 ≥ 94% on room air) or 4 (oxygen by mask or nasal prongs). - Hospitalized patients with severe disease can have score 5 (noninvasive ventilation or highflow oxygen), 6 (intubation and mechanical ventilation) or 7 (ventilation + additional organ support - pressors, RRT (renal replacement therapy), ECMO (extracorporeal membrane oxygenation)): - Patients who die have a score 8.
2. Percentage of patients with at least two-point improvement from baseline in clinical status on the 9-point ordinal scale.
3. Percentage of patients with at least one-point improvement from baseline in clinical status on the 9-point ordinal scale.
4. Percentage of patients with at least one-point deterioration from baseline in clinical status on the 9-point ordinal scale.
5. Time to improvement from baseline category to one less severe category of the 9-point ordinal scale.
6. Mean change from baseline in clinical status on the 9-point ordinal scale
7. Mortality rate
8. Proportion of patients requiring mechanical ventilation
9. Duration of hospitalization.
10. The time to discharge or to a NEWS2 score of ≤2 and maintained for 24 hours whichever comes first.
11. Change from baseline in NEWS2 score.
12. Change from baseline in SpO2/FiO2 ratio.
13. Proportion of patients with no oxygen therapy (no oxygen therapy is required if oxygen saturation ≥ 94% on room air)

1. Estado clínico según una escala ordinal de 9 puntos.
2. Porcentage de pacientes con al menos 2 puntos de mejora desde el basal en el estado clínico sobre la escala ordinal de 9 puntos.
3. Porcentage de pacientes con al menos 1 punto de mejora desde el basal en el estado clínico sobre la escala ordinal de 9 puntos.
4. Porcentage de pacientes con al menos 1 punto de deterioro desde el basal en el estado clínico sobre la escala ordinal de 9 puntos.
5. Tiempo de mejora desde la categoria basal a una categoría menos severa de la escala ordinal de 9 puntos.
6. Cambio medio desde el basal en el estado clínico sobre la escala ordinal de 9 puntos.
7. Tasa de mortalidad.
8. Proporción de pacientes que requieren ventilación mecánica.
9. Duración de la hospitalización.

Para demás variables secundarias refiérase al protocolo.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Day 15, Day 29
2. Baseline, Day 15, Day 29
3. Baseline, Day 15, Day 29
4. Baseline, Day 15, Day 29
5. 29 days
6. Baseline, Day 15, Day 29
7. Day 15, Day 29
8. 29 days
9. 29 days
10. 29 days
11. Baseline, Days 3, 5, 8, 11, 15, and 29
12. Baseline, Day 15, Day 29
13. Day 15, Day 29

1. Día15, Día 29
2. Basal, Día 15,Día 29
3. Basal, Día 15, Día 29
4. Basal, Día 15, Día 29
5. 29 dias
6. Basal, Día 15, Día 29
7. Día 15, Día 29
8. 29 dias
9. 29 dias
10. 29 dias
11. Basal, Día 3, 5, 8, 11, 15, y 29
12. Basal, Día 15, Día 29
13. Día 15, Día 29

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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

France

Germany

Italy

Spain

United Kingdom

United States

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

LVLS

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

332

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

Yes

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

Yes

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.4.2

For a multinational trial

F.4.2.1

In the EEA

269

F.4.2.2

In the whole clinical trial

402

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)

Standard of care

tratamiento estandard

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

2020-05-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-05-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-10-17

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IMP with orphan designation in the indication
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