Clinical Trials Register

Summary
EudraCT Number:	2019-002124-32
Sponsor's Protocol Code Number:	CUSA-081-HEM-01
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:	2020-01-10
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

2019-002124-32

A.3

Full title of the trial

READY 1: A Phase 3, Randomized, Double-Blind, Active and Placebo-Controlled Study on the use of CUSA-081 for Dysfunctional Central Venous Access Devices (CVADs)

READY 1: Estudio en fase III, aleatorizado, doble ciego, controlado con tratamiento activo y con placebo sobre el uso de CUSA-081 para dispositivos de acceso venoso central (DAVC) disfuncionales

A.3.1

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

A study of CUSA-081 (reteplase) to evaluate its activity on clots with central venous access devices.

Estudio con CUSA-081 (reteplasa) para evaluar su actividad en coágulos con dispositivos de acceso venoso central.

A.3.2

Name or abbreviated title of the trial where available

READY 1

A.4.1

Sponsor's protocol code number

CUSA-081-HEM-01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03594175

A.5.4

Other Identifiers

Name:

IND Number

Number:

128551

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	Chiesi Farmaceutici S.p.A.
B.1.3.4	Country	Italy
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	Chiesi Farmaceutici S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Chiesi Farmaceutici S.p.A.
B.5.2	Functional name of contact point	Clinical Program Manager
B.5.3	Address:
B.5.3.1	Street Address	Via Palermo 26/A
B.5.3.2	Town/ city	Parma
B.5.3.3	Post code	43122
B.5.3.4	Country	Italy
B.5.4	Telephone number	+3905211689560
B.5.6	E-mail	clinicaltrials_info@chiesi.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	RETAVASE®
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi USA, Inc., Cary, NC 27518
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	CUSA-081
D.3.2	Product code	CUSA-081
D.3.4	Pharmaceutical form	Lyophilisate and solvent for solution for injection
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	RETEPLASE
D.3.9.1	CAS number	133652-38-7
D.3.9.4	EV Substance Code	SUB10290MIG
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	0.35
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	CATHFLO® ACTIVASE®
D.2.1.1.2	Name of the Marketing Authorisation holder	Genentech Inc., South San Francisco, CA 94080
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Lyophilisate for solution for injection
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	ALTEPLASE
D.3.9.1	CAS number	105857-23-6
D.3.9.4	EV Substance Code	SUB05378MIG
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	1
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Catheter Occlusion Thrombosis

Trombosis de oclusión por catéter

E.1.1.1

Medical condition in easily understood language

Restoration of function to central venous access devices (CVADs)

Restauración de la función a los dispositivos de acceso venoso central (DAVC)

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

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 demonstrate the superiority of CUSA-081 compared to placebo in the rate of treatment success following a single administration with a dwell time up to 90 minutes. Treatment success is defined as restoration of CVAD functionality measured as the ability to withdraw 3 mL of blood and infuse 5 mL of saline.

Demostrar la superioridad de CUSA-081 comparado con el placebo en la tasa de éxito del tratamiento después de una única administración con un tiempo de permanencia de hasta 90 minutos. El éxito del tratamiento se define como la restauración de la funcionalidad del DAVC, medida como la capacidad para retirar 3 ml de sangre e infusionar 5 ml de solución salina.

E.2.2

Secondary objectives of the trial

1. To demonstrate the non-inferiority of CUSA-081 compared to alteplase in the rate of treatment success following a single administration with a dwell time up to 90 minutes;
2. To demonstrate the superiority of CUSA-081 compared to placebo in the rate of treatment success following a single administration with a dwell time up to 60 minutes;
3. To demonstrate the superiority of CUSA-081 compared to placebo in the rate of treatment success following up to two administrations with a dwell time up to 180 minutes;
4. To demonstrate the superiority of CUSA-081 compared to alteplase in the rate of treatment success following a single administration with a dwell time up to 90 minutes;
5. To evaluate the safety and tolerability of CUSA-081;
6. To evaluate the rate of recurrent catheter dysfunction defined as first re-occlusion within 30 days following administration of CUSA-081.

1. Demostrar la no inferioridad de CUSA-081 comparado con alteplasa en la tasa de éxito del tratamiento después de una única administración con un tiempo de permanencia de hasta 90 minutos.
2. Demostrar la superioridad de CUSA-081 comparado con el placebo en la tasa de éxito del tratamiento después de una única administración con un tiempo de permanencia de hasta 60 minutos.
3. Demostrar la superioridad de CUSA-081 comparado con el placebo en la tasa de éxito del tratamiento después de un máximo de dos administraciones con un tiempo de permanencia de hasta 180 minutos.
4. Demostrar la superioridad de CUSA-081 comparado con alteplasa en la tasa de éxito del tratamiento después de una única administración con un tiempo de permanencia de hasta 90 minutos.
5. Evaluar la seguridad y la tolerabilidad de CUSA-081.
6. Evaluar la tasa de recurrencia de la disfunción del catéter definida como la primera reoclusión en un plazo de 30 días después de la administración de CUSA 081.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Inability to have 3mL of blood withdrawn from the selected study catheter;
2. A single or multi-lumen CVAD, implanted ports or peripherally inserted central catheters (PICCs) in place for > 24 hours and documented as previously being patent and functional;
3. Ability to designate one dysfunctional lumen of a multi-lumen catheter to be used throughout the study for both study drug instillation and assessment of CVAD function;
4. Male and non-pregnant female subjects from all racial and ethnic groups 18 years of age and older;
5. Able to have fluids infused at the volume necessary to instill study drug into the CVAD (i.e., up to 2 mL);
6. Informed consent form (ICF) signed and dated indicating that the subject has been informed of and agreed with all pertinent aspects of the study and is willing to comply with all study requirements and procedures.
Note: To be eligible to enter and participate in the study, all female subjects must have a negative urine pregnancy test at screening (regardless of age or child bearing potential).

1. Incapacidad para que se le extraigan 3 ml de sangre desde el catéter del estudio seleccionado.
2. Un DAVC con una o múltiples luces, puertos implantados o catéteres centrales insertados periféricamente (CCIP) en el lugar durante > de 24 horas y documentados previamente como patentados y funcionales.
3. Capacidad para designar una luz disfuncional de un catéter de múltiples luces que se utilizará durante todo el estudio tanto para la instilación del medicamento del estudio como para la evaluación de la función del DAVC.
4. Hombres y mujeres no embarazadas de todos los grupos raciales y étnicos de 18 años de edad y mayores.
5. Capaz de recibir los líquidos a infundir al volumen necesario para la instilación del medicamento del estudio en el DAVC (es decir, hasta 2 ml).
6. Formulario de consentimiento informado (FCI) firmado y fechado que indique que el sujeto ha sido informado y está de acuerdo con todos los aspectos pertinentes del estudio y está dispuesto a cumplir con todos los requisitos del estudio y los procedimientos.

NOTA: Para ser elegible para participar y participar en el estudio, todas las mujeres deben tener una prueba de embarazo en orina negativa en el examen de detección (independientemente de la edad o el potencial de tener hijos).

E.4

Principal exclusion criteria

1. CVAD (any type) used for Hemodialysis;
2. CVAD known to be dysfunctional for more than 48 hours;
3. Reasonable evidence of mechanical or non-thrombotic occlusion in the selected study catheter (e.g., catheter malposition or migration, sutures, kinks, or precipitates causing obstruction), radiographic assessment is not required;
4. Known or suspected catheter-related bloodstream infection (CRBSI);
5. Use of any fibrinolytic agent or anticoagulant (e.g., alteplase, tenecteplase, reteplase, urokinase or heparin) within 24 hours prior to the treatment period (first instillation of study drug). Use of subcutaneous LMWH for prophylaxis of thromboembolic events is allowed;
6. Known to be at high risk for bleeding events or embolic complications in the opinion of the Investigator, or has a known condition for which bleeding constitutes a significant hazard (e.g.
recent stroke, recent intracranial or intraspinal surgery or serious head trauma, intracranial neoplasm, arteriovenous malformation or aneurysm, known bleeding diathesis);
7. Uncontrolled hypertension (systolic BP ≥160 or diastolic BP ≥110 mmHg) at screening;
8. Clinically unstable in the opinion of the site investigator;
9. Known to be pregnant or breastfeeding at screening;
10. Previously treated in this study (READY 1) or in study READY 2;
11. History of allergic reaction to reteplase, alteplase or vial ingredients (excipients or diluents);
12. Use of any investigational drug or experimental medical device within 28 days prior to treatment; non interventional observational studies participation is allowed;
13. Not mentally, socially or otherwise able to complete the trial assessments or not likely to survive beyond 30 days.

1. DAVC (cualquier tipo) utilizado para hemodiálisis.
2. DAVC que se sepa que es disfuncional durante más de 48 horas.
3. Indicios razonables de oclusión mecánica o no trombótica en el catéter del estudio seleccionado (p. ej., mala colocación o migración del catéter, suturas, pliegues o precipitados que causen obstrucción), no es necesaria evaluación radiográfica.
4. Antecedentes conocidos o sospecha de infección del torrente sanguíneo relacionada con el catéter (ITSRC).
5. Uso de cualquier fibrinolítico o anticoagulante (p. ej., alteplasa, tenecteplasa, reteplasa, urocinasa o heparina) en el plazo de 24 horas antes del periodo de tratamiento (primera instilación del medicamento del estudio). Se permite el uso de HBPM subcutánea para la profilaxis de acontecimientos tromboembólicos.
6. Se sabe que presenta un riesgo alto de acontecimientos hemorrágicos o complicaciones embólicas en opinión del investigador, o que tiene una afección conocida para la que la hemorragia constituye un riesgo significativo (p. ej., accidente cerebrovascular reciente, cirugía intracraneal o intraespinal reciente o traumatismo craneal grave, neoplasia intracraneal, malformación arteriovenosa o aneurisma, diátesis hemorrágica conocida).
7. Hipertensión no controlada (PA sistólica ≥160 o PA diastólica ≥110 mmHg) en la selección.
8. Clínicamente inestable en opinión del investigador del centro.
9. Se sabe que está embarazada o en periodo de lactancia en la selección.
10. Tratado previamente en este estudio (READY 1) o en el estudio READY 2.
11. Antecedentes de reacción alérgica a reteplasa, alteplasa o a los componentes del vial (excipientes o disolventes).
12. Uso de cualquier medicamento en investigación o dispositivo médico experimental en los 28 días previos al tratamiento; se permite la participación en estudios observacionales no intervencionistas.
13. No es mentalmente, socialmente o de cualquier otro modo capaz de completar las evaluaciones del ensayo o no es probable que sobreviva por encima de los 30 días.

E.5 End points

E.5.1

Primary end point(s)

Percentage of subjects who have treatment success following a single instillation of study drug (CUSA-081, placebo, or alteplase). Treatment success is defined as the restoration of CVAD functionality measured as the ability to withdraw 3 mL of blood and infuse 5 mL of saline.

Porcentaje de sujetos con éxito del tratamiento después de una única instilación del medicamento del estudio (CUSA-081, placebo o alteplasa) con un tiempo de permanencia de hasta 90 minutos. El éxito del tratamiento se define como la restauración de la funcionalidad del DAVC, medida como la capacidad para extraer 3 ml de sangre e infundir 5 ml de solución salina.

E.5.1.1

Timepoint(s) of evaluation of this end point

90 minutes

90 minutos

E.5.2

Secondary end point(s)

1. Percentage of subjects who have treatment success following a single instillation of study drug .
2. Percentage of subjects who have treatment success after up to two instillations of study drug.
3. The rate of recurrent catheter dysfunction defined as first re-occlusion.

1. Porcentaje de sujetos con éxito del tratamiento después de una única instilación del medicamento.
2. Porcentaje de sujetos con éxito del tratamiento después de un máximo de dos instilaciones.
3. La tasa de recurrencia de la disfunción del catéter se define como la primera reoclusión.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. 30 minutes, 60 minutes.
2. 120 minutes, 150 minutes, 180 minutes.
3. 30 days.

1. 30 minutos, 60 minutos
2. 120 minutos, 150 minutos, 180 minutos
3. 30 días

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)

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)

Yes

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

Argentina

Belgium

Brazil

Czech Republic

France

Poland

Romania

Spain

United States

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

Defined in the study protocol as the last 30-day (day 30 +/- 2 days) follow-up contact of the last subject who received study drug in the trial.

Definido en el protocolo del estudio como el último seguimiento de 30 días (día 30 +/- 2 días) del último sujeto que recibió el fármaco del estudio 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

E.8.9.2

In all countries concerned by the trial years

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

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:

561

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

280

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

216

F.4.2.2

In the whole clinical trial

841

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)

None

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

2020-04-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-16

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-07-10

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