Clinical Trials Register

Summary
EudraCT Number:	2013-001798-26
Sponsor's Protocol Code Number:	PROMETE
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-08-20
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

France - ANSM

A.2

EudraCT number

2013-001798-26

A.3

Full title of the trial

A multicenter, open-label, Prospective, randomized parallel group Phase III study investigating the benefit on Renal function of a CNI-free regimen with MyfOrtic® (mycophenolate sodium) and Certican® (everolimus) in coMparison to therapy with CErTican® (everolimus) and Prograf® (tacrolimus) in de novo rEnal transplant patients at 12 months post transplantation

A.3.1

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

A.4.1

Sponsor's protocol code number

PROMETE

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	CHU DE POITIERS
B.1.3.4	Country	France
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	chu de poitiers
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHU DE POITIERS
B.5.2	Functional name of contact point	FANNY ABRIAT
B.5.3	Address:
B.5.3.1	Street Address	DIORECTION DE LA RECHERCHE-2 RUE DE LA MILETRIE
B.5.3.2	Town/ city	POITIERS
B.5.3.4	Country	France

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	Myfortic®
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS PHARMA SAS
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Mycophenolic Acid
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.3.11 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.2.1.1.1	Trade name	PROGRAF®
D.2.1.1.2	Name of the Marketing Authorisation holder	ASTELLAS PHARMA
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Tacrolimus
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.3.11 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.2.1.1.1	Trade name	CERTICAN®
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS PHARMA SAS
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Everolimus
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.3.11 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: 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.2.1.1.1	Trade name	SIMULECT
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS EUROPHARM LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Basiliximab
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 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

Kidney transplantation

E.1.1.1

Medical condition in easily understood language

Kidney transplantation

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 evaluate the effects on the renal function at 12 months post-transplant, of a CNI free therapeutic strategy switching Prograf to Mycophenolic Acid at Month 3, in patients treated with a CNI combined Prograf and Everolimus regimen within the first 3 months after transplantation.

E.2.2

Secondary objectives of the trial

Patient and graft survival rate
Rejection.rate.
Occurrence of side effects.
Early discontinuation.
To assess by a differential proteomic approach (iTRAQ) the evolution of urinary biomarkers of tacrolimus nephrotoxicity before and after tacrolimus withdrawal

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

A genomic and proteomic approach to predict acute rejection, fibrosis progression and chronic transplant dysfunction in patients enrolled in PROMETE Study.
Version N°1 27/03/2013.

The main objective of this study is to determine whether urinary concentrations of ARNm, protein , and the transcriptomic profile of protocol biopsies at 3 months may be considered as a prognosis evidence to predict further acute rejection, chronic histological lesions and chronic graft dysfunction in patients enrolled in PROMETE Study.
With the specific objectives above:

1) To determine whether urinary rates of ARNm, CXCL 10 protein and Perforin ARNm evaluated at 3 months post-transplant may be considered as a sensible and specific non invasive prognosis test for further occurrence of an acute rejection within 3 to 12 months post-tranplantation .

2) To determine whether transcriptomic analysis of regular protocol biopsy at 3 months, may be considered as a sensible and sensitive prognostic test for further occurrence of an acute rejection within 3 to 12 months post-transplantation.

3) To determine whether urinary concentrations of ARNm, CXCL10 protein and Perforin ARNm evaluated at 3 months and/or transcriptomic profile of the regular protocol biopsy at 3 months may predict further development of graft fibrosis within 3 to 12 months post-transplant.

4) To determine if urinary concentrations of ARNm, CXCL10 protein and Perforin ARNm evaluated at 3 months and/or transcriptomic profile of the 3 months post-transplant protocol biopsy may predict further occurrence of
graft dysfunction according to the DFG estimated value within 3 and 12 months post-transplant.

E.3

Principal inclusion criteria

1) Males or females, aged ≥ 18 years and ≤ 65 years
2) End stage kidney disease and a suitable candidate for primary renal transplantation
3) Receiving a kidney transplant from a deceased or living donor
4) Female capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at screening, and are required to practice an approved method of birth control for the duration of the study and for a period of 8 weeks following discontinuation of study medication even where there has been a history of infertility
5) Total ischemia time below 30 hours.
6) Patients able to receive a first dose of tacrolimus and everolimus in the 24 hours following the reperfusion of the transplant.
7) Capable of understanding the purpose and risks of the study.
8) Fully informed and having given written informed consent (signed Informed Consent has been obtained).
9) Affiliation to the social security regimen

E.4

Principal exclusion criteria

1) More than one previous renal transplantation
2) Multi-organ recipients (e.g. kidney and pancreas) or previous transplant with any other organ, different from kidney
3) Patients receiving a kidney from a non-heart beating donor
4) Patients who are recipients of A-B-O incompatible transplants
5) Patients who are HIV positive or Hepatitis B surface antigen positive or Hepatitis C virus positive. Recipients of organs from donors with positive test for Hepatitis B surface antigen or Hepatitis C are excluded.
6) Patients who have been treated with one of the study drug for 4 weeks before Everolimus administration.
7) Patients with clinically significant infection requiring continued therapy which would interfere with the objectives of the study
8) TGI > 50%
9) Known allergy or contraindication to everolimus, tacrolimus, mycophenolic acid, basiliximab, corticosteroids or any of the product excipients.
10) Evidence of severe liver disease (incl. abnormal liver enzyme profil, i.e. AST, ALT or total bilirubin > 3 times UNL)
11) Severe hyperlipidemia defined by: total cholesterol ≥ 9,1 mmol/L (≥ 350 mg/dL) and/or hypertriglyceridemia ≥ 5,6 mmol/l (≥ 500 mg/dL)
12) Patients with leucopenia (leucocytes ≤ 3000 / mm3) or thrombocytopenia (platelets ≤ 75000/mm3)
13) Patients having cicatrisation problems.
14) Patients suffering from a peptic ulcer.
15) Currently participating in another clinical trial, and/or has taken an investigational drug within four weeks prior to enrollment.
16) Any form of substance abuse, psychiatric disorder or condition which, in the opinion of the investigator, may complicate communication with the investigator.
17) Unlikely to comply with the visits scheduled in the protocol.
18) Patients with a diagnosed cancer or history of cancer (except for basal-cell carcinoma) within 5 years prior to enrollment

E.5 End points

E.5.1

Primary end point(s)

Renal function assessed as glomerular filtration rate (GFR) – MDRD method.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 MONTHS

E.5.2

Secondary end point(s)

• survival without rejection.
Patient and graft survival rate
To assess acute rejection rate .
• To assess de novo Donor specific HLA antibody (DSA) occurrence
• To assess occurrence of treatment failure up to or at Month 12, treatment failure being defined as a composite endpoint of biopsy proven acute rejection, graft loss, death, loss to follow up (at least one condition must be present)

SAFETY criteria
• To assess renal function
• To assess evolution of renal function Side effects such as:
• The proportion of patients with occurrence of New Onset Diabetes Mellitus as defined by American Diabetic Association (ADA) criteria

E.5.2.1

Timepoint(s) of evaluation of this end point

Patient and graft survival rate at 12 months.
Rejection rates at 3 months and 12 months.
Renal function at 12 months.
DSA rate at 3, 6 and 12 months.
Side effects at each visit.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

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

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:

390

F.1.3

Elderly (>=65 years)

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

390

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

NONE

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-02-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-22

P. End of Trial
P.	End of Trial Status	Completed

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