Clinical Trials Register

Summary
EudraCT Number:	2018-004273-27
Sponsor's Protocol Code Number:	CUETO1801
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:	2019-01-18
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

2018-004273-27

A.3

Full title of the trial

Multicenter clinical trial with medical device associated with a drug in an authorised therapeutic use for the treatment of CVNMI evaluating the efficacy and tolerability of the adyuvant treatment with EMDA-MMC versus standard BCG and the efficacy of a urinary bio-marker MCM5 ADXBLADDER in the detection of tumor recurrence in patients with high grade CVNMI

Ensayo Clínico Multicéntrico con producto sanitario asociado a fármaco en uso terapéutico autorizado para el tratamiento de CVNMI evaluando la eficacia y tolerabilidad del tratamiento adyuvante con EMDA-MMC versus estándar BCG y la eficacia del bio-marcador urinario MCM5 ADXBLADDER® en la detección de recidiva tumoral en pacientes con CVNMI de Alto Grado”

A.3.1

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

Multicenter clinical trial with medical device associated with a drug in an authorised therapeutic use for the treatment of bladder cancer non muscle invasive evaluating the efficacy and tolerability of the adyuvant treatment with EMDA-MMC versus standard BCG and the efficacy of a urinary bio-marker MCM5 ADXBLADDER in the detection of tumor recurrence in patients with high grade bladder cancer non muscle invasive

A.4.1

Sponsor's protocol code number

CUETO1801

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	PRESURGY, S.
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	PRESURGY, S.L
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	PHYSION, SRL
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	ARQUER DIAGNOSTICS
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PRESURGY, S.L
B.5.2	Functional name of contact point	CAROLINA ALOS
B.5.3	Address:
B.5.3.1	Street Address	POLLENSA 2 OF 2
B.5.3.2	Town/ city	LAS ROZAS / MADRID
B.5.3.3	Post code	28290
B.5.3.4	Country	Spain
B.5.4	Telephone number	34916402087
B.5.5	Fax number	34916366610
B.5.6	E-mail	carolina@presurgy.com

D. IMP Identification
D.IMP: 1
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	MITOMICINA C
D.2.1.1.2	Name of the Marketing Authorisation holder	INIBSA HOSPITAL S.L.U
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	MITOMICINA C
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MITOMYCIN
D.3.9.1	CAS number	50-07-7
D.3.9.4	EV Substance Code	SUB09006MIG
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	10 to 40
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	Yes
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

bladder cancer non muscle invasive in high risk patients

cáncer de vejiga no músculo infiltrante en pacientes de alto riesgo

E.1.1.1

Medical condition in easily understood language

bladder cancer non muscle invasive in high risk patients

cáncer de vejiga no músculo infiltrante en pacientes de alto riesgo

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10029759
E.1.2	Term	Normal delivery
E.1.2	System Organ Class	100000004868

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 the adjuvant with EMDA-MMC (induction x6 weekly instillations and 1 year of maintenance) compared with the BCG standard (induction x6 weekly instillations and 1 year of maintenance) in the adjuvant treatment of High Grade NMLCC.

- To evaluate the efficacy of the urinary bio-marker LCM5 ADXBLADDER® in the detection of tumor recurrence, compared with urinary cytology + cystoscopy, during the follow-up of high-grade NMIBC treated with BCG or with adjuvant EMDA-MMC.

- Evaluar la eficacia de la adyuvancia con EMDA-MMC (inducción x6 instilaciones semanales y 1 año de mantenimiento) comparado con el estándar BCG (inducción x6 instilaciones semanales y 1 año de mantenimiento) en el tratamiento adyuvante del CVNMI de Alto Grado.

- Evaluar la eficacia del bio-marcador urinario MCM5 ADXBLADDER® en la detección de la recidiva tumoral, comparada con la Citología urinaria + cistoscopia, durante el seguimiento del CVNMI de Alto Grado tratado con BCG o con EMDA-MMC adyuvante.

E.2.2

Secondary objectives of the trial

- To assess the tolerance to adjuvant endovesical chemotherapy with EMDA-MMC compared to the BCG standard (induction x6 weekly instillations and 1 year of maintenance) in the adjuvant treatment of high-grade NMIBC.

- To assess the impact on quality of life of adjuvant endovesical chemotherapy with EMDA-MMC compared to the BCG standard (induction x6 weekly instillations and 1 year of maintenance) in the adjuvant treatment of high-grade NMIBC.

- Carry out a cost-effectiveness analysis of the routine implementation of the urinal biomarker MCM5 ADXBLADDER® compared to the standard follow-up with Urinary cytology + Cystoscopy in the High Grade CVNMI.

- Evaluar la tolerancia a la quimioterapia endovesical adyuvante con EMDA-MMC comparada con el estándar BCG (inducción x6 instilaciones semanales y 1 año de mantenimiento) en el tratamiento adyuvante del CVNMI de Alto Grado.

- Evaluar el impacto en calidad de vida de quimioterapia endovesical adyuvante con EMDA-MMC comparada con el estándar BCG (inducción x6 instilaciones semanales y 1 año de mantenimiento) en el tratamiento adyuvante del CVNMI de Alto Grado.

- Realizar un análisis de coste-efectividad de la implementación rutinaria del bio-marcador urinario MCM5 ADXBLADDER® comparado con el seguimiento estándar con Citología urinaria + Cistoscopia en el CVNMI de Alto Grado.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients older than 18 years and life expectancy ≥ 5 years.
- Patients able to give informed consent for the study.
- Patients with primary non-muscle infiltrating urothelial non-muscle metamorphosed (NMIBC), uni- or multi-focal, stages Ta and T1, High Grade (2004 WHO), including old G2 High Grade and all G3.
- Patients treated with optically complete TUR of the tumor and, when indicated by clinical guidelines, RE-RTU that must be performed within the first 6 weeks.
- Negative bladder random biopsies for Tcis
- Presence of own muscle in the TUR and / or in the RE-RTU.
- RE-RTU in all cases of T1 and also in Ta tumors when the initial TUR is incomplete or with absence of muscle in the sample.

- Pacientes mayores de 18 años y esperanza de vida ≥ 5 años.
- Pacientes capaces de dar consentimiento informado para el estudio.
- Pacientes con carcinoma urothelial no músculo infiltrante (CVNMI) primarios, uni- o multi-focales, estadíos Ta y T1, de Alto Grado (2004 WHO), incluyendo antiguos G2 Alto Grado y todos los G3.
- Pacientes tratados con RTU ópticamente completa del tumor y, cuando indicada por guía clínica, RE-RTU que deberá realizarse dentro de las primeras 6 semanas.
- Biopsias aleatorias vesicales negativas para Tcis
- Presencia de muscular propia en la RTU y/o en la RE-RTU.
- RE-RTU en todos los casos de T1 y también en tumores Ta cuando la RTU inicial sea incompleta o con ausencia de muscular en la muestra.

E.4

Principal exclusion criteria

Patients unable to give informed consent for their participation in the study.
- Patients with a history of allergic reactions to BCG or MMC.
- Patients with pacemakers or DICs.
- Previous history of bladder tumors.
- Antecedents of pelvic radiotherapy (bladder, prostate, rectum, vagina, uterus).
- Absence of own muscle in the sample (neither in RTU nor in RE-RTU).
- Patients with stage T1 who have not received RE-RTU.
- Patients with Tcis isolated or associated with papillary tumor.
- Presence of squamous cell carcinoma of the bladder or bladder adenocarcinoma.
- Stage tumors ≥T2.
- cN + and / or cM + tumors.
- Pregnant women.
Relative contraindications for the use of the EMDA system
- Urethral stricture.
- Giant prostatic lobe with bladder neck occlusion.
- Psychosis
- Alcoholism
- Active untreated urinary infection

- Pacientes incapaces de dar consentimiento informado para su participación en el estudio.
- Pacientes con historia de reacciones alérgicas a la BCG o MMC.
- Pacientes portadores de marcapasos o DICs.
- Historia previa de tumores vesicales.
- Antecedentes de radioterapia pélvica (vejiga, próstata, recto, vagina, útero).
- Ausencia de muscular propia en la muestra (ni en RTU ni en RE-RTU).
- Pacientes con estadío T1 que no hayan recibido RE-RTU.
- Pacientes con Tcis aislado o asociado a tumor papilar.
- Presencia de carcinoma epidermoide de vejiga o adenocarcinoma vesical puros.
- Tumores estadíos ≥T2.
- Tumores cN+ y/o cM+.
- Mujeres embarazadas.
Contraindicaciones relativas para el uso del sistema EMDA
- Estenosis de uretra.
- Lóbulo prostático gigante con oclusión del cuello vesical.
- Psicosis
- Alcoholismo
- Infección Urinaria activa no tratada

E.5 End points

E.5.1

Primary end point(s)

- Disease free survival (SLE).
- Detection rate (TD) of tumor recurrence with the MCM5 ADX BLADDER® bio-marker, compared with that obtained with standard cytology.

- Supervivencia libre de enfermedad (SLE).
- Tasa de detección (TD) de la recidiva tumoral con el bio-marcador MCM5 ADX BLADDER®, comparada con la obtenida con citología estándar.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients will undergo oncological follow-up and Quality of Life, with periodic visits, every 3 months during the first year (month 3, 6, 9 and 12) and every 6 months thereafter and until the end of the follow-up period of 5 years (month 18, 24, 30, 36, 42, 48, ... .60).

Los pacientes se someterán a un seguimiento oncológico y de Calidad de Vida, con Visitas periódicas, cada 3 meses durante el primer año (mes 3, 6, 9 y 12) y cada 6 meses posteriormente y hasta el final del periodo de seguimiento de 5 años (mes 18, 24, 30, 36, 42, 48,….60).

E.5.2

Secondary end point(s)

- Tumor recurrence rate.
- Free survival of tumor progression (SLP).
- Rate of tumor progression.
- Rate of completion of adjuvant treatment.
- Sensitivity, Specificity, VPN and VPP of the ADXBLAADER® bio-marker.
- Cost-efficiency evaluation of the use of the model developed for the follow-up of patients with high-grade NMIBP treated with adjuvant BCG or EMDA-MMC.
- Impact of adjuvant treatment on patient's quality of life (FACT-BL)
- Adverse effects, EA and EAS.

- Tasa de recidiva tumoral.
- Supervivencia libre de progresión tumoral (SLP).
- Tasa de progresión tumoral.
- Tasa de cumplimentación del tratamiento adyuvante.
- Sensibilidad, Especificidad, VPN y VPP del bio-marcador ADXBLAADER®.
- Evaluación coste-eficiencia de la utilización del modelo desarrollado para el seguimiento de pacientes con CVNMI de Alto Grado tratados con BCG o EMDA-MMC adyuvante.
- Impacto del tratamiento adyuvante en calidad de vida del paciente (FACT-BL)
- Efectos adversos, EA y EAS.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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

Yes

E.8.2.3.1

Comparator description

BCG

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

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

5 years follow up. End of clinical trial year 2023

5 años de seguimiento. Fin del ensayo a finales 2023

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:

180

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

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

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

230

F.4.2

For a multinational trial

F.4.2.1

In the EEA

230

F.4.2.2

In the whole clinical trial

230

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

ninguno

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

2019-04-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-04

P. End of Trial
P.	End of Trial Status	Ongoing

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