Clinical Trials Register

Summary
EudraCT Number:	2013-000796-32
Sponsor's Protocol Code Number:	185/13
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-03-08
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2013-000796-32

A.3

Full title of the trial

A multiple centre, randomised, open label, prospective clinical study to compare the efficacy and safety of a combination of tacrolimus with everolimus versus the combination of tacrolimus with MMF, administered concomitantly once a day in kidney transplantation

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

ADEVAM

A.4.1

Sponsor's protocol code number

185/13

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	Policlinico A. Gemelli
B.1.3.4	Country	Italy
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 pharma
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Policlinico Gemelli
B.5.2	Functional name of contact point	Surgery department
B.5.3	Address:
B.5.3.1	Street Address	Lgo Gemelli 8
B.5.3.2	Town/ city	Rome
B.5.3.3	Post code	00168
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390630155133
B.5.5	Fax number	+390630155224
B.5.6	E-mail	fcitterio@rm.unicatt.it

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
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	Netherlands
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, hard
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	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Advagraf
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	Netherlands
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, hard
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
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	CERTICAN
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: 4
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	CELLCEPT
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	CELLCEPT
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.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

Body processes [G] - Immune system processes [G12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10023438
E.1.2	Term	Kidney transplant
E.1.2	System Organ Class	100000004865

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 in the two immunosuppressive regimens the composite endpoint including: incidence of clinical + BPAR acute rejection at month 12, graft survival at month 12, percentage of patients with creatinine < 1.8 mg/ml at month 12, percentage of patients with steroid withdrawal at month 12, percentage of patients on assigned therapy at 12 month. The occurrence of at least one of these conditions causes the treatment failure

E.2.2

Secondary objectives of the trial

To compare the efficacy and safety profiles of the two immunosuppressive regimens.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Male or female patient over 18 years of age.
2) Male or female cadaveric donor over 18 years of age.
3) Female patients of child bearing potential agree to maintain effective birth control practice during the study and 3 months thereafter.
4) Patient has end stage kidney disease and is a suitable candidate for primary single renal transplantation.
5) Patient is receiving kidney transplant, from a cadaveric (not HLA identical) compatible ABO blood type.
6) Patient is capable of understanding the purpose and risks of the study, has been fully informed and has given written informed consent. Patient unable to write and/or read but who fully understands the oral information given by the investigator (or nominated representative) has given oral informed consent witnessed in writing by an independent person.

E.4

Principal exclusion criteria

1) Positive cross-match
2) Patient has an immunological high risk, defined as a PRA grade >20% in the previous 6 months and/or having a previous renal allograft
3) Patient has significant liver disease, defined as having during the past 30 days contiuously elevated ASAT (SGOT) and/or ALAT (SGPT) levels greater than 3 times the upper value of the normal range of the investigational site or is receiving a graft from a hepatitis C or B positive donor. (HBVAg+, HCVab+).
4) Patient has severe hypercholesterolemia (>350mg/dL, 9.1 mmol/dL) or severe Leucopenia (WBC < 4000 /mm3) and / or PTL < 100.000/mm.
5) Patient is pregnant or breast-feeding.
6) Patient is allergic or intolerant to steroids, macrolide antibiotics, mycophenolate mofetil, tacrolimus, sirolimus or everolimus.
7) Patient requires ongoing dosing with a systemic immunosuppressive drug at study entry for any reason other than kidney transplantation.
8) Patient or donor is known to be HIV positive.
9) Patient with malignancy or history of malignancy, except non-metastatic basal or squamous cell carcinoma of the skin that has been treated successfully.
10) Patient has significant, uncontrolled concomitant infections and/or severe diarrhoea, vomiting, active upper gastro-intestinal tract malabsorption or active peptic ulcer.
11) Patient is participating or has participated in another clinical trial and/or is taking or has been taking an investigational drug in the past 30 days.
12) Patient has previously received or is receiving an organ transplant other than kidney.
13) Patient is unlikely to comply with the visits scheduled in the protocol.
14) Patient has any form of substance abuse, psychiatric disorder or condition which, in the opinion of the investigator, may invalidate communication with the investigator.
15) BMI > 35, obesity.

E.5 End points

E.5.1

Primary end point(s)

Composite endpoint including:
• incidence of BPAR acute rejection at month 12,
• incidence of graft failure at month 12,
• percentage of patients with creatinine > 1.8 mg/ml at month 12.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 MONTHS

E.5.2

Secondary end point(s)

- Acute rejection: Time to first acute rejection; overall frequency of clinical acute rejections episodes; incidence of biopsy-proven acute rejections; incidence of and time to first corticosteroid-resistant rejection; severity of biopsy-proven acute rejections (Banff ’97 criteria)
- Patient and graft survival at month 12
- percentage of patients who resumed or never stopped steroids at month 12,
- percentage of patients who were converted from the assigned therapy at month 12.
- Renal function as assessed by calculated creatinine clearance (MDRD).
- Renal function as assessed by Ioexol determination at month 6 and 12 (optional)
- Incidence of adverse events at month 6 and 12
- Absolute change in serum lipids (cholesterol, HDL, triglycerides, statines use) at month 6 and 12
- Absolute change in blood pressure control (systolic BP, diastolic BP, number of antihypertensive medications) at month 6 and 12
- Absolute change in glucose metabolism (fasting glucose, glycosilated Hb, insuline or oral anti-diabetic use) at month 6 and 12
- Incidence of and time to delayed graft function
- Incidence of creeping creatinine above 30% from the lowest post-transplant creatinine (nadir creatinine)
- Composite failure index: BPAR + death + Gloss + lost to follow-up
- number of daily pills taken by the patient at month 12 (number of medication pills the patient is receiving for his/her treatment including all the medications)
- protocol renal allograft biopsy taken at time 0 and at month 12
- incidence of wound healing complications at month 6: superficial and deep wound infections, incisional hernia
- incidence of lymphocele at month 6, defined as any fluid collection evidenced by ultrasound .
- Pharmacokinetic AUC profiles of Advagraf and Everolimus obtained on days 7 and 14 (if possible)

E.5.2.1

Timepoint(s) of evaluation of this end point

12 MONTHS

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:

200

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2013-03-08.

Yes

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

260

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)

ROUTINE

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

2014-01-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-01

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

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