Clinical Trials Register

Summary
EudraCT Number:	2022-001417-39
Sponsor's Protocol Code Number:	FIBHGM-ECNC001-2022
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:	2023-01-10
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

2022-001417-39

A.3

Full title of the trial

A phase IIb, double-blind clinical trial to compare the nephroprotection of cilastatin versus placebo in patients undergoing debulking surgery with intraoperative hyperthermic intraperitoneal chemotherapy with cisplatin

Ensayo clínico fase IIb, doble ciego, para comparar la nefroprotección de cilastatina frente a placebo en pacientes sometidos a cirugía de citorreducción con quimioterapia intraperitoneal intraoperatoria hipertérmica con cisplatino

A.3.1

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

To compare cilastatin vs placebo in renal protection in patients undergoing debulking surgery with intraoperative hyperthermic intraperitoneal chemotherapy with cisplatin

Comparar Cilastatina frente a placebo en la protección renal en pacientes sometidos a cirugía de citorreducción con quimioterapia intraperitoneal intraoperatoria hipertérmica con cisplatino

A.4.1

Sponsor's protocol code number

FIBHGM-ECNC001-2022

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 del Hospital Gregorio Marañón (FIBHGM)
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	Fundación para la investigación biomédica del Hospital Gregorio Marañón (FIBHGM)
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 del Hospital Gregorio Marañón (FIBHGM)
B.5.2	Functional name of contact point	María de la Cruz
B.5.3	Address:
B.5.3.1	Street Address	Dr. Esquerdo, 46
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28007
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3491 426 51 15
B.5.6	E-mail	ucaicec@fibhgm.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	No
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	Cilastatina
D.3.2	Product code	Cilastatina
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraperitoneal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cilastatin
D.3.9.2	Current sponsor code	FIBHGM-ECNC001-2022
D.3.9.4	EV Substance Code	SUB06264MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.5
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	Powder and solvent for solution for injection
D.8.4	Route of administration of the placebo	Intraperitoneal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Reduction of acute renal damage (days 1-7) (creatinine levels and KDIGO scale) in patients treated with CRS+HIPEC-cisplatin during the immediate postoperative period.

Reducción del daño renal agudo (días 1-7) (niveles de creatinina y escala KDIGO) en pacientes tratados con CRS+HIPEC-cisplatino durante el postoperatorio inmediato.

E.1.1.1

Medical condition in easily understood language

acute kidney damage

daño renal agudo

E.1.1.2

Therapeutic area

Not possible to specify

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 efficacy of cilastatin in reducing acute kidney damage (days 1-7) (creatinine levels and KDIGO scale) in patients treated with CRS+HIPEC-cisplatin during the immediate postoperative period.

Demostrar la eficacia de cilastatina en la reducción del daño renal agudo (días 1-7) (niveles de creatinina y escala KDIGO) en pacientes tratados con CRS+HIPEC-cisplatino durante el postoperatorio inmediato.

E.2.2

Secondary objectives of the trial

- To study the pharmacokinetics of cisplatin with/without cilastatin during the HIPEC procedure.
- Analyze the number of subjects with adverse effects and serious adverse effects during the follow-up time (7 days
- Evolution of ARF in patients with/without cilastatin with a total follow-up of 14 days.
- Evaluation of preoperative, intraoperative and postoperative factors that influence renal damage in CRS+HIPEC–cisplatin.
- To study the usefulness of the determination of urinary H202 in the prediction of the appearance of DR by cisplatin after the HIPEC procedure.
- To study the changes in urinary FasL after the HIPEC procedure as an early measure of DR intensity, as well as the specificity of the mechanism of action of the nephroprotection expected with cilastatin.

-Estudiar la farmacocinética del cisplatino con/sin cilastatina durante el procedimiento de HIPEC.
-Analizar el número de sujetos con efectos adversos y efectos adversos graves durante el tiempo de seguimiento (7 días
-Evolución del FRA en pacientes con/sin cilastatina con un seguimiento total de 14d
-Evaluación de factores preoperatorios, intraoperatorios y postoperatorios que influyan en el daño renal en la CRS+HIPEC–cisplatino.
-Estudiar la utilidad de la determinación de H202 urinario en la predicción de la aparición de DR por cisplatino tras el procedimiento de HIPEC.
-Estudiar los cambios en FasL urinario tras el procedimiento de HIPEC como medida precoz de intensidad del DR, así como de la especificidad del mecanismo de acción de la nefroprotección esperada con cilastatina.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Age: adult patients from 18-75 years.
2.Sex: female.
3. Eastern Cooperative Oncology Group Performance status (ECOG PS) ≤ 2
4. General situation of the patient: patient suitable for major surgery, with values of creatinine, bilirubin, blood series in a range close to normal (Hb>10g/dl, leucos >3000/ml, neutrals >1000/ml, platelets >100,000 /ml).
5.Patients evaluated in the Anesthesia office and considered suitable for the intervention.
6. Signed informed consent.
7. Disease confined to the abdomen: CRS+HIPEC is not contemplated in patients with lung or bone metastases, etc. If evaluated in patients with limited numbers of hematogenous, splenic, or hepatic metastases. If lymphatic spread close to the tumor or distant intra-abdominal spread is assessed, if complete resection is possible. Stage IVA (FIGO) of epithelial ovarian carcinoma in debut, due to pleural effusion + mediastinal lymphatic metastases, or splenic metastases is an indication for neoadjuvant chemotherapy; and if there is a response, it can be evaluated for CRS + HIPEC.

1.Edad: pacientes adultos a partir de 18-75 años.
2.Sexo: femenino.
3.Eastern Cooperative Oncology Group Performance status (ECOG PS)≤ 2
4.Situación general del paciente: paciente apto para cirugía mayor, con valores de creatinina, bilirrubina, series sanguíneas en rango próximo a la normalidad (Hb>10g/dl, leucos > 3000/ml, neutros > 1000/ml, plaquetas > 100.000/ml).
5.Pacientes evaluados en la consulta de Anestesia y considerados aptos para la intervención.
6.Consentimiento informado firmado.
7.Enfermedad confinada en el abdomen: no se contempla una CRS+HIPEC en pacientes con metástasis pulmonares, óseas, etc. Si se valora en pacientes con metástasis hematógenas esplénicas o hepáticas en número limitado. Si se valora en diseminación linfática próxima al tumor, o lejana intra-abdominal, si es posible la resección completa. El estadio IVA (FIGO) de carcinoma epitelial de ovario en debut, por derrame pleural + metástasis linfáticas mediastínicas, o metástasis esplénicas es indicación de quimioterapia neoadyuvante; y si hay respuesta puede valorarse para CRS + HIPEC.
8.Evaluación en Comité Multidisciplinar: se realiza PCI radiológico y se estima posibilidades de citorreducción completa, indicándose de CRS + HIPEC.

E.4

Principal exclusion criteria

1. Non-acceptance to participate in the clinical trial.
2.ECOG PS > 2.
3.Not suitable for major surgery.
4. Disease not limited to the abdomen or with signs that it cannot be optimally cytoreduced (intestinal obstruction, biliary obstruction, ureteral obstruction, diffuse involvement of the small intestine or mesentery).
5. Allergy to platinum.

1.No aceptación de participar en el ensayo clínico.
2.ECOG PS > 2.
3.No apta para cirugía mayor.
4.Enfermedad no limitada al abdomen o con signos de no poder ser citorreducida de forma óptima (obstrucción intestinal, obstrucción biliar, obstrucción ureteral, afectación difusa del intestino delgado o el mesenterio).
5.Alergia a platinos.

E.5 End points

E.5.1

Primary end point(s)

Percentage of patients with renal failure at 7 days* (if there is renal damage, follow-up until postoperative day 14) measured through creatinine values and the KDIGO classification. Renal failure is defined as an increase in serum creatinine of 1.5 to 1.9 times baseline, or an increase in serum creatinine by ≥0.3 mg/dL (≥26.5 µmol/L), or a decrease in urine output <0.5 mL/kg/hour for 6 to 12 hours.

Porcentaje de pacientes con fallo renal a los 7 días* (Si hay daño renal seguimiento hasta día 14 postoperatorio) medido a través de los valores de creatinina y la clasificación KDIGO. Se define fallo renal como aumento de la creatinina sérica de 1,5 a 1,9 veces el valor inicial, o aumento de la creatinina sérica en ≥0,3 mg/dL (≥26,5 µmol/L), o reducción de la producción de orina a <0,5 ml/kg/hora durante 6 a 12 horas.

E.5.1.1

Timepoint(s) of evaluation of this end point

7 days

7 días

E.5.2

Secondary end point(s)

1. Differences in plasma pharmacokinetic variables of cisplatin during the HIPEC procedure between cilastatin-treated and placebo-treated patients.
2. Percentage of patients experiencing serious adverse events, adverse events related to study treatment, and adverse events occurring during the study.
3. Comparison of ARF in patients with/without cilastatin with a total follow-up of 14 days
4. Comparison of urinary H202 values between patients who suffer DR and patients who do not.
5. Comparison of preoperative, intraoperative and postoperative factors between patients who suffer from kidney damage and patients who do not.
6. Comparison of urinary FasL between patients with renal damage and patients without.

1.Diferencias en las variables farmacocinéticas en plasma del cisplatino durante el procedimiento HIPEC entre los pacientes tratados con cilastatina y los tratados con placebo.
2.Porcentaje de pacientes que tienen efectos adversos graves, acontecimientos adversos relacionados con el tratamiento del estudio y acontecimientos adversos producidos durante el estudio.
3.Comparación del FRA en pacientes con/sin cilastatina con un seguimiento total de 14d
4.Comparación de los valores de H202 urinario entre pacientes que sufren DR y pacientes que no lo sufren.
5.Comparación de los factores preoperatorios, intraoperatorios y postoperatorios entre pacientes que sufren daño renal y pacientes que no.
6.Comparación de FasL urinario entre pacientes que sufren daño renal y pacientes que no.

E.5.2.1

Timepoint(s) of evaluation of this end point

7-14 days

7-14 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

E.6.4

Safety

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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

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

LPLS

ultima visita del ultimo sujeto

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:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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

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

2023-05-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-05-18

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

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