Clinical Trials Register

Summary
EudraCT Number:	2017-002293-39
Sponsor's Protocol Code Number:	BIOIMMUN
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:	2017-08-02
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

2017-002293-39

A.3

Full title of the trial

MULTICENTER, RANDOMIZED STUDY, TO EVALUATE THE EFFECTIVENESS OF INDIVIDUALIZATION OF IMMUNOLOGICAL RISK BASED ON SELECTIVE BIOMARKERS (DISPARITY OF HLA EPLETS AND ELISPOT-γ) TO OPTIMIZE IMMUNOSUPPRESSIVE TREATMENT IN LIVING DONOR KIDNEY RECIPIENTS

ESTUDIO MULTICÉNTRICO Y ALEATORIZADO PARA EVALUAR LA EFICACIA DE LA INDIVIDUALIZACIÓN DEL RIESGO INMUNOLÓGICO BASADO EN BIOMARCADORES SELECTIVOS (DISPARIDAD DE EPLETOS HLA Y ELISPOT-γ) PARA OPTIMIZAR EL TRATAMIENTO INMUNOSUPRESOR EN PACIENTES TRASPLANTADOS RENALES DE DONANTE VIVO

A.3.1

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

STUDY TO OPTIMIZE IMMUNOSUPPRESSIVE MEDICATION AS A RESULT OF TWO MARKERS IN PATIENTS WHO RECEIVE A RENAL TRANSPLANTATION OF A LIVE DONOR

ESTUDIO PARA OPTIMIZAR LA MEDICACIÓN INMUNOSUPRESORA EN FUNCIÓN DEL RESULTADO DE DOS MARCADORES EN PACIENTES QUE RECIBEN UN TRASPLANTE RENAL DE UN DONANTE VIVO

A.3.2

Name or abbreviated title of the trial where available

BIOIMMUN

A.4.1

Sponsor's protocol code number

BIOIMMUN

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	ORIOL BESTARD
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	Departament de Salut (Generalitat de Catalunya)
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 UNIVERSITARI DE BELLVITGE-IDIBELL
B.5.2	Functional name of contact point	CAROLINA POLO
B.5.3	Address:
B.5.3.1	Street Address	FEIXA LLARGA
B.5.3.2	Town/ city	L'HOSPITALET DE LLOBREGAT
B.5.3.3	Post code	08907
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34932607385
B.5.5	Fax number	+34932607960
B.5.6	E-mail	cpolo@idibell.cat

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.2.1.2	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
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	TACROLIMUS
D.3.9.1	CAS number	104987-11-3
D.3.9.2	Current sponsor code	TACROLIMUS
D.3.9.3	Other descriptive name	TACROLIMUS
D.3.9.4	EV Substance Code	SUB10797MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.1
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.IMP: 2
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.2.1.2	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	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	MYCOPHENOLATE MOFETIL
D.3.9.2	Current sponsor code	MYCOPHENOLATE MOFETIL
D.3.9.3	Other descriptive name	MYCOPHENOLATE MOFETIL
D.3.9.4	EV Substance Code	SUB03360MIG
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	1000 to 1500
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.IMP: 3
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.2.1.2	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	Solution for infusion
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	BASILIXIMAB
D.3.9.1	CAS number	179045-86-4
D.3.9.2	Current sponsor code	BASILIXIMAB
D.3.9.3	Other descriptive name	BASILIXIMAB
D.3.9.4	EV Substance Code	SUB12468MIG
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	20
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	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.IMP: 4
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.2.1.2	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	Solution for infusion
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	METHYLPREDNISOLONE
D.3.9.2	Current sponsor code	METHYLPREDNISOLONE
D.3.9.3	Other descriptive name	METHYLPREDNISOLONE
D.3.9.4	EV Substance Code	SUB08872MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	500
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.IMP: 5
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.2.1.2	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	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	PREDNISONE
D.3.9.2	Current sponsor code	PREDNISONE
D.3.9.3	Other descriptive name	PREDNISONE
D.3.9.4	EV Substance Code	SUB10020MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	60
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.IMP: 6
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.2.1.2	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	Solution for infusion
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	ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN FROM RABBITS
D.3.9.2	Current sponsor code	ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN FROM RABBITS
D.3.9.3	Other descriptive name	ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN FROM RABBITS
D.3.9.4	EV Substance Code	SUB21246
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	3
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	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

PROPHYLAXIS OF REJECTION AFTER KIDNEY TRANSPLANTATION

PROFILAXIS DE RECHAZO TRAS EL TRASPLANTE RENAL

E.1.1.1

Medical condition in easily understood language

PROPHYLAXIS OF REJECTION AFTER KIDNEY TRANSPLANTATION

PROFILAXIS DE RECHAZO TRAS EL TRASPLANTE RENAL

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Investigative Techniques [E05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10023439
E.1.2	Term	Kidney transplant rejection
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of the trial is to determine the effect of individualizing immunosuppressive therapy based on stratification of baseline immunological risk according to 2 biomarkers (ELISPOT IFN-G d-sp and HLA Eplets Missmatch), in a composed end-point: loss of renal function, incidence of acute rejection and development of dnDSA at 2 years of follow-up in renal transplant patients of living donor compared to patients followed according to standard non-individualized immunosuppressive regimen

El objetivo principal del ensayo es determinar el efecto de individualizar la terapia inmunosupresora en base a la estratificación del riesgo inmunológico basal según 2 biomarcadores (ELISPOT IFN-G d-sp y Mismatch de epletos HLA), en un end-point compuesto por la pérdida de función renal, incidencia de rechazo agudo y desarrollo de dnDSA a los 2 años de seguimiento en pacientes trasplantados renales de donante vivo comparado con los pacientes seguidos según régimen inmunosupresor estándar no individualizado

E.2.2

Secondary objectives of the trial

To assess whether individualized stratification of immunological risk and therapeutic optimization reduces:
- patient mortality
- loss of renal graft
- the development of subclinical and chronic rejection determined in protocol biopsies at 3 and 24 months
- Opportunistic infections
- the metabolopathies derived from the treatment (diabetes mellitus, dyslipidemia and hypertension)
- malignancies (cutaneous and non-cutaneous cancer) at 2 years of follow-up
- the economic cost.
Evaluate changes:
- in the allogenic d-sp response over the 2-year follow-up (dnDSA, ELISPOT IFN- and d-sp, cytokines in urine)
- the transcriptional profile of rejection risk according to the kSORT test
- the antiviral cellular response to CMV, EBV and VBK viruses.

Evaluar si la estratificación individualizada del riesgo inmunológico y optimización terapéutica reduce:
- la mortalidad del paciente
- la pérdida de injerto renal
- el desarrollo de rechazo subclínico y crónico asesorado en biopsias de protocolo a los 3 y 24 meses
- las infecciones oportunistas
- las metabolopatías derivadas del tratamiento (diabetes mellitus, dislipemia y HTA)
- la malignidad (cáncer cutáneo y no cutáneo) a los 2 años de seguimiento
- el coste económico.
Evaluar los cambios:
- en la respuesta alogénica d-sp a lo largo de los 2 años de seguimiento (dnDSA, ELISPOT IFN-y d-sp, citoquinas en orina)
- el perfil transcripcional de riesgo de rechazo según el test de kSORT
- la respuesta celular antiviral enfrente los virus CMV, VEB i VBK.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Adult men and women (≥ 18 years).
2) Receptors of a first kidney transplant from a living donor.
3) AB0 compatible transplant.
4) Patients with a documented PRA <20% and absence of anti-HLA class I and class II antibodies by solid phase assay (Luminex®).
5) Patients who agree to participate in the Assay by signing the Informed Consent specific to this study.
6) Potentially fertile women should use high-reliability contraceptive methods (Pearl-Index <1) to prevent pregnancy for the duration of the study and up to 6 weeks after the end of their treatment with Mycophenolate Mofetil (MMF). Potentially Fertile Women include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not post-menopausal (defined as amenorrhoea ≥ 12 consecutive months, or women who are receiving hormone replacement therapy with a documented level of follicle stimulating hormone (FSH)> 35 mlU / ml). Potentially Fertile Women should have a pregnancy test with a negative result performed within 72 hours prior to the start of the trial.
7) Sexually active (including vasectomized) males who are receiving MMF treatment should accept the use of barrier contraception during MMF treatment and during the 90 days thereafter. Potentially fertile couples of these patients should use a reliable method of contraception during the same period, in order to minimize the risk of pregnancy.
8) Patients should agree not to donate blood during MMF treatment and for 6 weeks thereafter. Males should not donate sperm during MMF treatment and up to 90 days after finishing MMF.

1) Hombres y mujeres adultos (≥ 18 años).
2) Receptores de un primer trasplante renal procedente de un donante vivo.
3) Trasplante AB0 compatible.
4) Pacientes con un PARA documentado <20% y ausencia de anticuerpos anti-HLA de clase I y de clase II mediante ensayo de fase sólida (Luminex®).
5) Pacientes que aceptan participar en el Ensayo mediante la firma del Consentimiento Informado específico de este estudio.
6) Las Mujeres Potencialmente Fértiles deben utilizar métodos anticonceptivos de alta fiabilidad (Pearl-Index < 1) de cara a evitar el embarazo durante toda la duración del estudio y hasta 6 semanas tras la finalización de su tratamiento con Micofenolato Mofetil (MMF). Las Mujeres Potencialmente Fértiles incluyen cualquier mujer que ha experimentado menarquia y que no se haya sometido a una esterilización quirúrgica con éxito (histerectomía, ligadura de trompas bilateral u ooforectomía bilateral) o que no sea post-menopáusica (definida como amenorrea ≥ 12 meses consecutivos, o mujeres que están recibiendo tratamiento hormonal sustitutivo con un nivel documentado de hormona estimulante folicular (FSH) >35 mlU/ml). Las Mujeres Potencialmente Fértiles deben tener una prueba de embarazo con resultado negativo realizada en las 72 horas previas al inicio del ensayo.
7) Los varones sexualmente activos (incluidos los vasectomizados) que estén recibiendo tratamiento con MMF deben aceptar el uso de métodos anticonceptivos de barrera durante el tratamiento con MMF y durante los 90 días posteriores. Las parejas potencialmente fértiles de estos pacientes deben utilizar un método anticonceptivo fiable durante el mismo periodo, de cara a minimizar el riesgo de embarazo.
8) Los pacientes deben aceptar no donar sangre durante el tratamiento con MMF y durante las 6 semanas posteriores. Los varones no deben hacer una donación de esperma durante el tratamiento con MMF y hasta 90 días después de finalizarlo.

E.4

Principal exclusion criteria

1) Patients with documented PRA> 20% and / or anti-HLA class I and / or class II antibodies detectable by solid phase assay (Luminex®).
2) Cross Match positive result.
3) Patients receiving a graft from a deceased donor.
4) Patients who have undergone a previous solid organ transplant (including renal transplantation) or who are going to receive another solid organ transplant concomitantly.
5) Patients with any of the following basic kidney diseases:
Primary focal and segmental glomerulosclerosis
Atypical Uremic Hemolytic Syndrome (aHUS) / Thrombotic Thrombotic Syndrome Thrombocytopenic.
6) Patients with chronic Hepatitis B virus (HBV) infection and / or active infection with Hepatitis C virus (positive PCR result) at the time of transplantation.
7) Patients with known Human Immunodeficiency Virus (HIV) infection.
8) Patients with active systemic infection requiring continued antibiotic administration.
9) Patients with any neoplasia except localized skin cancer receiving appropriate treatment.
10) Patients with severe anemia (hemoglobin <6g / dl), leukopenia (WBC <2500 / mm3) and / or thrombocytopenia (platelets <80,000 / mm3).
11) Hemodynamically unstable patients with hemoglobin levels> 6g / dl.
12) Patients with intestinal pathology or severe diarrhea that may decrease absorption according to medical criteria.
13) Patients with known hypersensitivity to any of the drugs used in this study.
14) Patients who have received any investigational drug within 30 days prior to their inclusion in this study.
15) Potentially fertile women who do not agree to use reliable contraceptive measures during the trial, who are pregnant, breastfeeding or have a positive pregnancy test at the time of enrollment.
16) Patients who are legally detained in an official institution.

1) Pacientes con un PRA documentado >20% y/o anticuerpos anti-HLA de clase I y/o clase II detectables mediante ensayo de fase sólida (Luminex®).
2) Resultado positivo de Cross Match.
3) Pacientes que reciban un injerto procedente de un donante cadáver.
4) Pacientes que se hayan sometido a un trasplante previo de órgano sólido (incluyendo el trasplante renal) o que vayan a recibir otro trasplante de órgano sólido de forma concomitante.
5) Pacientes con alguna de las siguientes enfermedades renales de base:
a. Glomeruloesclerosis focal y segmentaria primaria
b. Síndrome Hemolítico Urémico Atípico (aHUS) / Síndrome Púrpura Trombótica Trombocitopénica.
6) Pacientes con infección crónica por el virus de la Hepatitis B (HBV) y/o infección activa por el virus de la Hepatitis C (resultado de PCR positivo) en el momento del trasplante.
7) Pacientes con infección por el virus de la Inmunodeficiencia Humana (HIV) conocida.
8) Pacientes con infección sistémica activa que requiera la administración continuada de antibióticos.
9) Pacientes con alguna neoplasia excepto el cáncer de piel localizado y que esté recibiendo tratamiento adecuado.
10) Pacientes con anemia grave (hemoglobina <6g/dl), leucopenia (WBC <2500/mm3) y/o trombocitopenia (plaquetas <80.000/mm3).
11) Pacientes hemodinámicamente inestables aunque presenten unos niveles de hemoglobina >6g/dl.
12) Pacientes con patología intestinal o diarrea grave que pueda disminuir la absorción según criterio médico.
13) Pacientes con hipersensibilidad conocida a alguno de los fármacos usados en este estudio.
14) Pacientes que hayan recibido cualquier fármaco en investigación en los 30 días previos a su inclusión en este estudio.
15) Mujeres Potencialmente Fértiles que no estén de acuerdo en utilizar medidas anticonceptivas fiables durante el ensayo, que estén embarazadas, en periodo de lactancia o que presenten una prueba de embarazo positiva en el momento de su inclusión en el estudio.
16) Pacientes que están legalmente detenidos en una institución oficial.

E.5 End points

E.5.1

Primary end point(s)

The main variable is a composite variable at 2 years of follow-up, including loss of renal function, incidence of acute clinical rejection, and development of "de novo" (dn) Donor Specific Antibodies (DSA).

La variable principal es una variable compuesta valorada a los 2 años de seguimiento que incluye la pérdida de función renal, incidencia de rechazo agudo clínico y el desarrollo de “de novo” (dn) Donor Specific Antibodies (DSA).

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months

24 meses

E.5.2

Secondary end point(s)

Secondary variables:
A- Mortality from any cause at 24 months
B- Loss of renal graft at 24 months
C- Incidence and severity of subclinical and chronic rejection (according to protocol biopsies at 3 and 24 months)
D- Incidence of opportunistic infections at 24 months
E- Incidence of treatment-derived metabolopathies (diabetes mellitus, dyslipidemia and hypertension) at 24 months
F- Incidence of cardiovascular events at 24 months
G- Incidence of malignancy (cutaneous and non-cutaneous cancer) at 24 months
H- Proportion of patients who maintain treatment according to the protocol at the end of the trial.
I- Changes in the immune response at 24 months according to biomarkers:
- allogeneic response (dn-DSA, ELISPOT IFN-G d-sp, Memory B cell Elispot, urinary cytokines CXCL9 and CXCL10)

- transcriptional profile in blood of risk of rejection according to the kSORT test

Antiviral cell response to CMV, EBV, VBK; NKG2

J- Economic cost.
K- Serious adverse reactions (serious adverse events with possible causal relationship with immunosuppressive treatment).

Variables secundarias:
a- Mortalidad por cualquier causa a los 24 meses
b- Pérdida de injerto renal a 24 meses
c- Incidencia y gravedad del rechazo subclínico y crónico (según biopsias de protocolo a los 3 y 24 meses)
d- Incidencia de infecciones oportunistas a 24 meses
e- Incidencia de metabolopatías derivadas del tratamiento (diabetes mellitus, dislipemia y HTA) a 24 meses
f- Incidencia de eventos cardiovasculares a los 24 meses
g- Incidencia de malignidad (cáncer cutáneo y no cutáneo) a los 24 meses
h- Proporción de pacientes que mantienen el tratamiento según el protocolo al final del ensayo.
i- Cambios en la respuesta inmunológica a los 24 meses según los biomarcadores:
- respuesta alogénica (dn-DSA, ELISPOT IFN-G d-sp, Memory B cell Elispot, citoquinas en orina CXCL9 y CXCL10)

- perfil transcripcional en sangre de riesgo de rechazo según el test kSORT

- respuesta celular antivírica frente a virus CMV, VEB, VBK; NKG2

j- Coste económico.
k- Reacciones adversas graves (acontecimientos adversos graves con posible relación de causalidad con el tratamiento inmunosupresor).

E.5.2.1

Timepoint(s) of evaluation of this end point

24 months

24 meses

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

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

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

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

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:

100

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

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

164

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

2017-10-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-09

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

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