Clinical Trials Register

Summary
EudraCT Number:	2014-002643-18
Sponsor's Protocol Code Number:	REDUCE
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:	2018-08-02
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

2014-002643-18

A.3

Full title of the trial

REDUCE - Multicenter, prospective, randomized study investigating the efficacy and safety of a reduced immunosuppressive therapy with tacrolimus once daily in comparison to standard triple immunosuppression in senior renal transplant recipients

REDUCE - Estudio multicéntrico, prospectivo y aleatorizado que investiga la Eficacia y Seguridad de una terapia inmunosupresora reducida con tacrólimus en comparación con la inmunosupresión triple estándar en receptores de trasplante renal mayores

A.3.1

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

REDUCE - study in a number of european centers for investigation of efficacy and safety of a reduced immunosuppressive therapy with tacrolimus once daily in comparison to standard therapy with 3 immunosuppressive drugs in senior renal transplant recipients

REDUCE-estudio en centros europeos para la investigación sobre la eficacia y seguridad de una terapia inmosupresora reducida con tracolimus una vez al día en comparación con la terapia estándar con 3 medicamentos inmunosupresores en receptores de trasplante renal mayores

A.3.2

Name or abbreviated title of the trial where available

REDUCE

A.4.1

Sponsor's protocol code number

REDUCE

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02453867

A.5.4

Other Identifiers

Name:

Centre for Evidence in Transplantation Approval

Number:

CET010

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	Charité Universitätsmedizin Berlin
B.1.3.4	Country	Germany
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	Astellas Europe (unrestricted grant)
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	Charité Universitätsmedizin Berlin
B.5.2	Functional name of contact point	Division of Nephrology
B.5.3	Address:
B.5.3.1	Street Address	Charitéplatz 1
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	10117
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049(0)30450514072
B.5.5	Fax number	0049(0)30450514902
B.5.6	E-mail	senior.reducetrial@charite.de

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	Advagraf 0.5 mg prolonged-release hard capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma Europe B.V
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Prolonged-release capsule, hard
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.3.9.4	EV Substance Code	SUB10797MIG
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	0.5
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	Yes
D.3.11.13.1	Other medicinal product type	Immunosuppressant
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	Germany
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	Mycophenolate
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mofetil mycophenolate
D.3.9.1	CAS number	128794-94-5
D.3.9.3	Other descriptive name	MYCOPHENOLATE MOFETIL
D.3.9.4	EV Substance Code	SUB03360MIG
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	Yes
D.3.11.13.1	Other medicinal product type	Immunosuppressant
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	Germany
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	Mycophenolate
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Mycophenolate sodium
D.3.9.1	CAS number	37415-62-6
D.3.9.3	Other descriptive name	MYCOPHENOLATE SODIUM
D.3.9.4	EV Substance Code	SUB16447MIG
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	Yes
D.3.11.13.1	Other medicinal product type	Immunosuppressant
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	Germany
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	Intravenous use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	prednisolone
D.3.9.1	CAS number	50-24-8
D.3.9.3	Other descriptive name	PREDNISOLONE
D.3.9.4	EV Substance Code	SUB10018MIG
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.2.1.1.1	Trade name	Advagraf 1 mg prolonged-release hard capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma Europe B.V
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Prolonged-release capsule, hard
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.3.9.4	EV Substance Code	SUB10797MIG
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	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	Yes
D.3.11.13.1	Other medicinal product type	Immunosuppressant
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.2.1.1.1	Trade name	Advagraf 3 mg prolonged-release hard capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma Europe B.V
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Prolonged-release capsule, hard
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.3.9.4	EV Substance Code	SUB10797MIG
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	3
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	Yes
D.3.11.13.1	Other medicinal product type	Immunosuppressant
D.IMP: 7
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	Advagraf 5 mg prolonged-release hard capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma Europe B.V
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Prolonged-release capsule, hard
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.3.9.4	EV Substance Code	SUB10797MIG
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	Yes
D.3.11.13.1	Other medicinal product type	Immunosuppressant
D.IMP: 8
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	Germany
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	Intravenous use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	methylprednisolone
D.3.9.1	CAS number	83-43-2
D.3.9.3	Other descriptive name	METHYLPREDNISOLONE
D.3.9.4	EV Substance Code	SUB08872MIG
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Immunosuppression after kidney transplantion in elderly patients ≥65 years of age

Inmunosupresión después del trasplante renal en pacientes ≥65 años

E.1.1.1

Medical condition in easily understood language

Immunosuppression after kidney transplantion in elderly patients ≥65 years of age

Inmunosupresión después del trasplante renal en pacientes ≥65 años

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10062016
E.1.2	Term	Immunosuppression
E.1.2	System Organ Class	10021428 - Immune system disorders

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	10054990
E.1.2	Term	Immunodeficiency secondary to organ transplantation
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10074474
E.1.2	Term	Transplantation complications
E.1.2	System Organ Class	100000004863

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 establish efficacy and safety of a reduced immunosuppressive therapy with tacrolimus once daily for senior (>65 years of age) renal transplant recipients.
Main objective:
Non-inferiority of a reduced immunosuppressive therapy compared to standard therapy regarding a combined efficacy endpoint (BPAR, graft loss and death) between randomization (at month 3 post-transplant) and month 12 post-transplant

Establecer la eficacia y seguridad de una terapia inmunosupresora reducida, con tacrólimus una vez al día en receptores mayores (>65 años) de un trasplante renal.
Objetivo principal:
Demostrar la no inferioridad de una terapia inmunosupresora reducida en comparación con la terapia estándar con respecto a un criterio de valoración combinado de eficacia (BPAR, pérdida del injerto y muerte) entre la aleatorización y el mes 12 tras el trasplante.

E.2.2

Secondary objectives of the trial

Secondary objectives:
- Incidence and time of graft loss
- Incidence and time of death
- Incidence and time of biopsy proven rejection
- Evaluation infections: opportunistic (CMV, BKV), severe infections between study groups
- Evaluation of kidney function by estimation of eGFR (CKD-EPI) between study Groups
- Evaluation of hospitalisations
- Evaluation of HLA antibody development and donor specific antibody (DSA) development
- Evaluation of adverse and severe adverse events
- Evaluation of post transplant Diabetes mellitus
- Evaluation of laboratory result bundles (blood counts, etc.)
- Evaluation of concomittant medication
- Evaluation of quality of life measures
- Assessment of Frailty

Infecciones graves (confirmadas por IPr) después de la aleatorización
•Infecciones oportunistas (confirmadas por el IP) después de la aleatorización, en particular:
oInfección por CMV y Viremia por CMV
oNefropatía BK y Viremia BK
oObjetivo combinado Viremia por CMV y BK
•Diferencia de la función renal estimada por CKD-EPI [2], determinada entre los grupos de tratamiento a los 6, 9 y 12 meses después del trasplante.
•Hospitalizaciones, por infecciones y e infecciones oportunistas (confirmadas por IP) después de la aleatorización.
•Desarrollo de anticuerpos anti-HLA circulantes, anticuerpos no HLA y / o desarrollo de anticuerpos específicos contra el donante (DSA) después de la aleatorización
•Evaluación de la fragilidad
•Evaluación y comparación de la calidad de vida (según la evaluación del cuestionario PROMIS Profile 29) y la carga de síntomas médicos (según la evaluación del cuestionario MTSODS) entre los grupos en los meses 3 y 12 postrasplante

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Protocol chapter 4.1.1.
Inclusion criteria
1. Males or females, aged ≥65 years and participating in the European SENIOR transplant registry
2. Patients who received a renal allograft 3 – 3.5 months prior to randomization.
3. Patient must have received primary or secondary renal allograft from a blood group compatible donor
4. Standard criteria donors (SCD), expanded criteria donors (ECD), donors after cardiac death (DCD) and living donors (LD) are eligible
5. Patients who are willing and able to participate in the study and from whom written informed consent has been obtained
6. Patients on continuous standard triple therapy with tacrolimus once daily (Advagraf®, trough level 5-15ng/ml) in combination with mycophenolate (either ≥1.0g/day MMF or ≥720mg/d EC-MPS) and steroids (≥5mg prednisolone or equivalent) since transplantation
7. Stable graft function with serum creatinine ≤2.5 mg/dl.
8. Patients with low to standard immunological risk, who had a PRA below 20% or 20% and no known donor specific antibodies (DSA) at transplantation

1. Hombres o mujeres, mayores de 65 años y que participan en el registro europeo de trasplantes SENIOR
2. Pacientes que recibieron un aloinjerto renal 3 - 3.5 meses antes de la aleatorización.
3. El paciente debe haber recibido un primer o segundo trasplante renal, de un donante de grupo sanguíneo compatible.
4. Son elegibles donantes según criterios estándar (SCD), donantes según criterios ampliados (ECD), donantes después de muerte cardiaca (DCD) y donantes vivos (LD)
5. Pacientes que estén dispuestos y puedan participar en el estudio y de quienes se haya obtenido el consentimiento informado por escrito
6. Pacientes con tratamiento triple estándar continuo con tacrólimus una vez al día (Advagraf®, nivel mínimo 5-15ng / ml) en combinación con micofenolato (ya sea MMF ≥1.0g / día o EC-MPS ≥720mg / d) y esteroides (≥5mg de prednisona o equivalente) desde el trasplante
7. Función de injerto estable con creatinina sérica ≤2,5 mg / dl.
8. Pacientes con riesgo inmunológico bajo o estándar, que tenían un PRA ≤ 20% y ningún anticuerpo donante específico (DSA) antes del trasplante

E.4

Principal exclusion criteria

Protocol chapter 4.1.2. Exclusion criteria
1. Patient with mental dysfunction or inability to comply with the study protocol
2. Patients, who - according to the investigator - require for medical reasons (e.g. previous rejections) continuous triple therapy or a different tacrolimus exposure
3. Multi-organ recipients (other solid organ (e.g. pancreas) or bone marrow)
4. Blood group ABO-incompatible allografts
5. Patients who suffered from severe T-cell mediated rejection (at least Banff II acute rejection), recurrent acute rejection (>1 episode), or steroid resistant rejection post-transplant
6. History of antibody-mediated rejection (acute or chronic)
7. History of rejection 2 months prior to inclusion
8. Documented presence of donor specific antibodies (DSA) according to local lab results at baseline
9. Panel reactive antibody (PRA) >20% prior to transplantation, measured according to local standard
10. Patients receiving or having received Sirolimus, Everolimus, Azathioprine, Belatacept or Cyclophosphamide within 3 months prior to enrolment
11. Patients having received any other induction therapy than Basiliximab (e.g. depleting polyclonal antithymocyte antibodies (ATG), OKT3, Alemtuzumab)
12. Patients with proteinuria >1.0 g/day (or >1.0 g/g creatinine) at screening or having experienced nephrotic syndrome due to recurrence of focal segmental glomerulosclerosis (FSGS)
13. History of alcohol or drug abuse with less than 6 months of sobriety
14. Patient with a known hereditary immunodeficiency
15. Patient with active malignancy posttransplant with the exception of local, non-invasive, fully excised, cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, or cervical carcinoma in situ
16. Patients with clinically symptomatic congestive heart failure or symptomatic coronary artery disease
17. Patients with documented (either by serology and/or nuclear acid testing (NAT) clinically active infections (e.g. with a known Hepatitis B, Hepatitis C, HIV, CMV or BK virus infection). Patients who do not have been screened in the previous 6 months, should be screened to confirm seronegativity before enrolment.
18. Participation in any other investigational clinical trial 3 months before participation in this study, except the SENIOR transplant registry
19. Patients with leukopenia (<2500 cells/mcl) or neutropenia (<1500 cells/mcl)
20. Patients with thrombocytopenia (<100 cells/nl)
21. Patients with liver transaminases or bilirubin values > 3x normal values
22. Any significant diseases or clinically significant findings, including psychiatric and behavioural problems, medical history and/or physical examination findings that would in the opinion of the investigator preclude the patient from participating in the study.
23. Patients who have been institutionalized by official or court order

1. Paciente con disfunción mental o incapacidad para cumplir con el protocolo del estudio
2. Los pacientes que, según el investigador, requieren por razones médicas (por ejemplo, rechazos anteriores) una terapia triple continua o una exposición diferente al tacrólimus
3. Receptores de trasplante de órganos múltiple (otros órganos sólidos, por ejemplo, páncreas o médula ósea)
4. Receptores de aloinjertos de grupo sanguíneo ABO incompatibles
5. Pacientes que sufrieron rechazo agudo mediado por células T (≥ Banff II rechazo agudo), rechazo agudo recurrente (> 1 episodio) o rechazo resistente a esteroides después del trasplante
6. Historia del rechazo mediado por anticuerpos (agudo o crónico)
7. Antecedentes de rechazo 2 meses antes de la inclusión
8. Presencia documentada de anticuerpos donante específicos (DSA) según los resultados de laboratorio locales en la visita basal
9. Panel Reactive de Anticuerpos (PRA)> 20% antes del trasplante, medido de acuerdo con la normativa local
10. Pacientes que reciben o han recibido Sirolimus, Everolimus, Azathioprine, Belatacept o Cyclophosphamide dentro de los 3 meses previos a la inclusión
11. Pacientes que han recibido cualquier tratamiento de inducción excepto Basiliximab (por ejemplo, los anticuerpos antitimocíticos policlonales (ATG), OKT3, Alemtuzumab)
12. Pacientes con proteinuria > 1.0 g / día (o > 1.0 g / g de creatinina) en la selección o que han experimentado síndrome nefrótico debido a la recurrencia de glomeruloesclerosis segmentaria focal (GEFS)
13. Historia del abuso de alcohol o drogas con menos de 6 meses de sobriedad
14. Paciente con inmunodeficiencia hereditaria conocida
15. Paciente con neoplasia activa tras el trasplante, con la excepción de carcinoma basocelular cutáneo, carcinoma cutáneo de células escamosas local no invasivo, totalmente extirpado, carcinoma cutáneo de células escamosas o carcinoma cervical in situ
16. Pacientes con insuficiencia cardíaca congestiva clínicamente sintomática o enfermedad coronaria sintomática
17. Pacientes con infecciones clínicamente activas documentadas (ya sea por serología y / o pruebas de ácidos nucleicos (NAT) (por ejemplo, con una infección conocida por el virus de la hepatitis B, hepatitis C, VIH, CMV o BK). Los pacientes que no se han sometido a exámenes de detección en los últimos 6 meses, deben someterse a un cribado para confirmar la seronegatividad antes de la inclusión
18. Participación en cualquier otro ensayo clínico de investigación 3 meses antes de la participación en este estudio, excepto el registro de trasplante SENIOR
19. Pacientes con leucopenia (<2500 células / mcl ) o neutropenia (<1500 células / mcl)
20. Pacientes con trombocitopenia (<100 células / nl)
21. Pacientes con transaminasas hepáticas o valores de bilirrubina > 3x valores normales
22. Cualquier enfermedad significativa o hallazgos clínicamente significativos, incluyendo problemas psiquiátricos y de comportamiento, antecedentes médicos y / o resultados de exámenes físicos que, en opinión del investigador, impidan que el paciente participe en el estudio.
23. Pacientes que han sido institucionalizados por orden oficial o judicial

E.5 End points

E.5.1

Primary end point(s)

Combined efficacy endpoint (BPAR, graft loss and death) between randomization (month 3 post-transpant) and month 12 posttransplant

Eficacia combinada (BPAR, la pérdida de injerto y la muerte) entre la aleatorización (mes 3 post-trasplante) y el mes 12 post-trasplante

E.5.1.1

Timepoint(s) of evaluation of this end point

Month 12 after transplantation.

12 meses después del trasplante

E.5.2

Secondary end point(s)

- Severe after randomization
- Opportunistic infections after randomization, in particular
- CMV Infection and CMV Viremia
- BK Nephropathy and BK Viremia
- Combined endpoint CMV and BK Viremia
- Difference in renal function as estimated by the CKD-EPI [34], determined between treatment groups at month 6, 9 and 12 posttransplant.
- Hospitalisations, hospitalisations for infections and hospitalisations for opportunistic infections (as confirmed by the investigator) after randomization
- Time to efficacy failure (defined as any patient experiencing death, graft failure, BPAR) after randomization
- Incidence and time of BPAR and/or graft loss, of graft loss and/or death, graft loss alone, death alone
- Incidence and time to BPAR (Banff grade of at least IA) and Borderline rejection(s) after randomization according to BANFF classes 2013
- Incidence and time to clinically suspected and treated rejection episodes (treated acute rejection despite the absence of confirmatory evidence on a biopsy) and to steroid-resistant rejections, recurrent rejections, antibody-treated rejections and antibody-mediated acute rejection after randomization
- Proportion of severity grades of the first episode of BPAR (Banff grade) occurring after randomization
- Development of circulating anti-HLA-antibodies, non HLA-antibodies and/or de novo donor specific antibodies (DSA)
- Change of renal function (according to CKD-EPI formula) from randomization to month 12 after transplantation.
- Comparison of the GFR-slope between randomization and month 12 (according to CKD-EPI-formula) between groups
- Incidence of patients with different stages of chronic kidney disease (CKD) according to CKD-EPI formula and with suboptimal GFR (<60ml/min, <45ml/min and <30 ml/min according to CKD-EPI formula)
- Comparison of the incidence of patients with improved renal function compared to baseline at randomization
- Differences between treatment groups after randomization with respect to the incidence of adverse events (AEs), serious Adverse events (SAEs), predefined AEs, vital signs and potentially clinically significant laboratory measures
- Incidence of any malignancy and infection after randomization
- Differences of hospitalisation days between treatment groups after randomization and in hospitalisation days due to infections and opportunistic infections (as confirmed by the investigator) between treatment groups after randomization
- Incidence and time to premature discontinuation of randomly assigned treatment (as confirmed by the investigator) for any reason
- Comparison of reasons for treatment discontinuation or treatment changes (as confirmed by the investigator)
- Incidence of posttransplant diabetes (PTDM) at month 12 as defined by need for any antidiabetic agent (oral or insulin) and/or HbA1c >48 mmol/mol (>6,5%) in a patient with no prior medical history of diabetes before transplantation and of posttransplant hyperglycemia within 9 months after randomization as defined by a fasting plasma glucose ≥126 mg/dL, and/or afternoon capillary glucose ≥200mg/dl with or without insulin requirement or need for an oral antidiabetic agent in a patient with no prior medical history of diabetes
- Incidences of Hb1Ac elevation a) >42 mmol/mol (>6.0%), b) >48 mmol/mol (>6,5%) and c) >53 mmol/mol (>7.0% ) at month 12 post transplantation
- Differences in the parameters of glucose control including HbA1c and blood lipids (total Cholesterol, LDL, HDL, Trigylcrides)
- Difference in blood pressure and blood pressure medication
- Difference in cardiovascular events defined as any cardiac event, stroke or peripheral vascular disease including invasive therapeutic cardiovascular interventions after randomization
- Difference in cardiovascular risk as estimated by the cardiovascular risk calculator for renal transplant recipients[35]
- Difference in the incidence of anemia as reported as adverse events, or the use of erythropoietin stimulating agents, or haemoglobin value <10g/dl after randomization and at month 12 posttransplant
- Difference in the use of erythropoietin stimulating agents after randomization and at month 12 posttransplant
- Incidence of patients with a low haemoglobin <10.0g/dl, or <11g/dl at month 12 after transplantation
- Difference in leucocyte and neutrophil counts at 12 months after transplantation
- Difference in the incidence of leucopenia (<3,5/nl) and neutropenia (<1,5/nl) and the use of colony stimulating factors after randomization and of patients with a leucopenia <4,0/nl, <3,0/nl or <2,5/nl after randomization
- IgG levels
- Incidence of Bone disease and/ fractures as confirmed by the investigator, differences in height between groups
- Assessment of frailty
- Evaluation and comparison of quality of life (as assessed by PROMIS Profile 29 questionnaire) and medical symptom burden (as assessed by MTSODS questionnaire) between groups at month 3 and 12 posttransplant

Severos después aleatorización
Infec. oportunistas después aleatorización, en particular
Infección CMV y Viremia por CMV
Nefropatía BK y Viremia BK
Objetivo combinado Viremia por CMV y BK
Diferencia función renal estimada por CKD-EPI determinada entre grupos de trat. a los 6, 9-12 meses después trasplante Hospitalizaciones ,hospitalizaciones por infecciones e infecciones oportunistas (confirmadas IP) después de aleatorización
Tiempo hasta fracaso de eficacia (definido como cualquier pac. que experimente muerte, fallo del injerto, BPAR) después de la aleatorización
Incidencia/tiempo BPAR y/o pérdida injerto, pérdida injerto y/o muerte, solo pérdida injerto, solo muert
Incidencia/tiempo hasta BPAR (grado Banff como mínimo IA) y rechazo/s límite después de aleatorización según clases de BANFF 2013
Incidencia/tiempo hasta episodios de rechazo clínicamente sospechados y tratados (rechazo agudo tratado a pesar de ausencia de evidencia confirmatoria en una biopsia) y hasta los rechazos resistentes a esteroides, rechazos recurrentes, rechazos tratados con anticuerpos y rechazo agudo mediado por anticuerpos después de la aleatorización
Proporción grados severidad primer episodio de BPAR (grado de Banff) que ocurre después de aleatorización
Desarrollo anticuerpos anti-HLA circulantes, anticuerpos no HLA y/o desarrollo anticuerpos específicos contra el donante (DSA
Cambio función renal (segúnfórmula CKD-EPI) desde leatorización hasta mes 12 después del trasplante
Comparación pendiente GFR entre aleatorización y mes 12 (según fórmula CKD-EPI) entre grupos
Incidencia pacientes con diferentes estados de enfermedad renal crónica (ERC) según fórmula CKD-EPI y con GFR subóptima (<60ml/min, <45ml/min y <30ml/ min según fórmula CKD-EPI)
Comparación incidencia de pacientes con función renal mejorada encomparación con el basal en el momento de aleatorización
Diferencias entre grupos tratamiento después de aleatorización respecto a la incidencia de AAs,AAGs, AAs predefinidos, constantes vitales y medidas de laboratorio potencial y clínicamente significativas
Incidencia de cualquier tumor maligno7infección después de leatorización- Diferencia de días hospitalización entre grupos de tratamiento después de aleatorización y días de hospitalización debido a infecciones/infecciones oportunistas (confirmadas por investigador) entre grupos de tratamiento después de aleatorización
Incidencia/ tiempo hasta interrupción prematura tratamiento asignado aleatoriamente (confirmado por IP) por cualquier motivo
Comparación de las razones para interrupción tratamiento o cambio de tratamiento (confirmado investigador
Incidencia Diabetes post-trasplante (DMPT) en mes 12, definida por necesidad de cualquier agente antidiabético (oral/insulina) y/o HbA1c >48 mmol/mol (>6,5%) en un paciente sin antecedentes médicos de diabetes antes del trasplante y de hiperglucemia post-trasplante dentro de 9 meses después de aleatorización, definida por glucosa en plasma en ayunas ≥126 mg/dL y/o glucosa capilar por la tarde ≥200 mg/dL con/sin requerimiento de insulina o necesidad de un agente antidiabético oral en un paciente sin antecedentes médicos previos de diabetes
Incidencias elevación de Hb1Ac a) >42 mmol/mol (>6,0%), b) >48 mmol/mol (>6,5%) y c) >53 mmol/mol (>7,0%) en mes 12 post-trasplante
Diferencias en los parámetros de control glucosa incluyendo HbA1c y en lípidos en sangre (colesterol total, LDL, HDL, triglicéridos)
Diferencia en presión arterial y medicación para presión arterial
Diferencia en eventos cardiovasculares definidos como cualquier evento cardíaco, accidente cerebrovascular o enfermedad vascular periférica incluyendo intervenciones cardiovasculares terapéuticas invasivas después dealeatorización Diferencia en el riesgo cardiovascular según lo estimado por la calculadora de riesgo cardiovascular para receptores de trasplante renal
Diferencia en incidencia de anemia reportada como AA, o el uso de agentes estimuladores de la eritropoyetina, o valor de hemoglobina <10 g/dL después de aleatorización y en mes 12 post-trasplante
Diferencia en el uso de agentes estimulantes de la eritropoyetina después de aleatorización y en el mes 12 post-trasplante- Incidencia de pacientes con baja hemoglobina <10,0 g/dL o <11 g/dL en el mes 12 después trasplante
Diferencia en el recuento de leucocitos y neutrófilos a los 12 meses después trasplante- Diferencia en la incidencia de leucopenia (<3,5/nl) y neutropenia (<1,5/nl) y el uso de factores estimulantes de colonias después de aleatorización y pacientes con leucopenia <4,0/nl, <3,0/nl o <2,5/nl después de aleatorización Niveles de IgG
Incidencia enfermedad ósea/fracturas confirmadas por el investigador, diferencias en altura entre los grupos- Evaluación de fragilidad- Evaluación y comparación de calidad de vida (según evaluación del cuestionario PROMIS Profile 29) y carga de síntomas médicos (según evaluación cuestionario MTSODS) entre los grupos en los meses 3-12 post-trasplante

E.5.2.1

Timepoint(s) of evaluation of this end point

Month 12 after transplantation

12 meses después del trasplante

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

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)

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Combinación de tacrolimus (Advagraf), micofenolato, esteroides

Combination of tacrolimus (Advagraf), mycophenolate, steroids

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

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 - The study ends when the last data element is available from the last subject to complete the month 12 visit.

UVUP - El estudio finalizada cuando todos los datos de la visita del mes 12 del último paciente incluido, están disponibles.

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

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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

400

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

400

F.4.2.2

In the whole clinical trial

400

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)

All patients will be followed up yearly in the SENIOR registry for up to 10 years. The SENIOR registry is registered at ClinicalTrials.gov: NCT02558452. This registry is built to observe 1000 elderly european kidney transplant recipients ≥65 years of age from Transplantation for 10 years. Thereafter the patients will stay within the follow up programs of each transplantation Center.

Durante 10 años, todos los pacientes incluidos en el ensayo serán seguidos anualmente en el registro SENIOR. El registro SENIOR está incluido en ClinicalTrials.gov: NCT01558452. Este registro está diseñado para observar a 1000 receptores de transplantes de rinón europeos de edad avanzada ≥65 años de edad durante 10 años.
Posteriormente, los pacientes permanecerán dentro de los programas de seguimiento de cada centro de trasplante.

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

2018-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-04

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-05-25

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