Clinical Trials Register

Summary
EudraCT Number:	2012-002857-41
Sponsor's Protocol Code Number:	BORTEJECT
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-18
Trial results	View 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

Austria - BASG

A.2

EudraCT number

2012-002857-41

A.3

Full title of the trial

Bortezomib in late antibody-mediated kidney transplant rejection (BORTEJECT Study)

Bortezomib bei später Antikörper-mediierten Nierentransplantatabstoßung (BORTEJECT Studie)

A.3.1

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

Bortezomib for the treatment of late transplant rejection after kidney transplantation

Bortezomib in der Behandlung später Transplantatabstoßung nach Nierentransplantation

A.3.2

Name or abbreviated title of the trial where available

Bortezomib in late transplant rejection

Bortezomib bei später Transplantatabstoßung

A.4.1

Sponsor's protocol code number

BORTEJECT

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	Universitätsklinik für Innere Medizin III, Medizinische Universität Wien
B.1.3.4	Country	Austria
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	Universitätsklinik für Innere Medizin III, Medizinische Universität Wien
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinik für Innere Medizin III, Medizinische Universität Wien
B.5.2	Functional name of contact point	Abt. für Nephrologie und Dialyse
B.5.3	Address:
B.5.3.1	Street Address	Währinger Gürtel 18-20
B.5.3.2	Town/ city	Wien
B.5.3.3	Post code	1090
B.5.3.4	Country	Austria
B.5.4	Telephone number	004301404004363
B.5.5	Fax number	0043014040039302
B.5.6	E-mail	georg.boehmig@meduniwien.ac.at

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	Velcade
D.2.1.1.2	Name of the Marketing Authorisation holder	JANSSEN-CILAG
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Velcade
D.3.2	Product code	ATC group: L01XX32
D.3.4	Pharmaceutical form	Solution for injection/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	BORTEZOMIB
D.3.9.1	CAS number	179324-69-7
D.3.9.4	EV Substance Code	SUB20020
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3,5 mg
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	Valaciclovir Sandoz 250 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz GesmbH
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Valaciclovir Sandoz 250 mg
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	VALACICLOVIR
D.3.9.1	CAS number	124832-26-4
D.3.9.4	EV Substance Code	SUB00003MIG
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	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Late antibody-mediated kidney allograft rejection

Späte Antikörper-mediierte Nierentransplantat-Abstoßung

E.1.1.1

Medical condition in easily understood language

Kidney transplant rejection

Nierentransplantat-Abstoßung

E.1.1.2

Therapeutic area

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

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

The primary objective of the planned non-commercial investigator-initiated and -driven study is to assess the efficiency of the innovative concept of proteasome inhibition in the treatment of late AMR. Our primary hypothesis is that, by inhibiting alloantibody production bortezomib halts the progression of ongoing graft injury and dysfunction.

Im Rahmen dieser prospektiven randomisierten kontrollierten (akademischen; nicht kommerziellen) Studie soll erstmals untersucht werden, ob durch eine Therapie mit dem Proteasom-Inhibitor Bortezomib die Progression einer AMR-getriggerten Nierentransplantat-Funktionsstörung aufgehalten werden kann (Teil B; klinische Prüfung). Die Rekrutierung eines Kollektivs von Patienten/Patientinnen mit später AMR soll dabei in einem ersten Teil der Studie (Teil A) im Rahmen eines Vor-Screenings (Antikörper-Screening; bioptisches Screening nach Identifikation zirkulierender DSA) erfolgen. Alternativhypothese: Bortezomib hemmt die Progression einer Nierentransplantat-Dysfunktion im Rahmen einer späten AMR. Nullhypothese: Bortezomib beeinflusst die Progression einer Nierentransplantat-Progression bei später AMR nicht.

E.2.2

Secondary objectives of the trial

not applicable

nicht zutreffend

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Voluntary written informed consent
Age >18 years
Functioning allograft after ≥180 days
eGFR >20 ml/min/1.73 m2
Serological results
HLA class I and/or II DSA-positive
Index BX results
At least one of the following features (with or without C4d in PTC):
Glomerulitis – PTCitis - transplant glomerulopathy - PTC BM lamellation

Freiwillige Einverständnis, Informed Consent
Alter >18 Jahre
Funktionierendes Transplantat nach ≥180 Tagen
eGFR >20 ml/min/1.73 m2
Serologische Resultate
HLA Klasse I und/oder II DSA-positiv
Index BX Resultate:
Zumindest eines der folgenden Features (mit oder ohne C4d in den PTC):
Glomerulitis – PTCitis - Transplant Glomerulopathie - PTC BM Lamellierung

E.4

Principal exclusion criteria

Laboratory tests
Thrombocytopenia <30 G/l within 2 weeks before enrolment
Neutrophil count <1 G/l within 2 weeks before enrolment
Clinical evaluation
Peripheral neuropathy ≥grade 2
Index BX results
Patients actively participating in another clinical trial
Female subject is pregnant or lactating*
Acute rejection treatment <1 month before screening
Acute deterioration of graft function due to suspected acute rejection
Active viral, bacterial or fungal infection precluding bortezomib treatment
Active malignant disease precluding intensified immunosuppressive therapy
Serious medical or psychiatric illness likely to interfere with participation in the study*
Documented intolerance of Bortezomib, boron or mannitol
T-cell-mediated rejection classified Banff grade >I
De novo or recurrent severe thrombotic microangiopathy
Polyoma virus nephropathy
De novo or recurrent glomerulonephritis in the allograft

E.5 End points

E.5.1

Primary end point(s)

Course of calculated GFR over 2 years (0, 6, 12, 18, 24 months)

E.5.1.1

Timepoint(s) of evaluation of this end point

0, 6, 12, 18, 24 months after randomization

E.5.2

Secondary end point(s)

HLA antibody levels (0, 6, 12, 18, 24 months)
Maximum and sum of MFI of DSA
Number of DSA
Broadness of sensitization (virtual PRA)
Measured GFR (Cr-EDTA method) at 0 and 24 months
Protein excretion (protein/creatinine ratio) at 0, 6, 12, 18, and 24 months
Graft and patient survival (12 and 24 months after randomization)
Occurrence of biopsy-proven acute rejection necessitating rejection treatment
Acute AMR score in a protocol BX performed 24 months after randomization
Chronic AMR score in a protocol BX performed 24 months after randomization
Peripheral blood leukocyte typing (immune cell subpopulations) at 0, 4, 8, 20 weeks, and 6, 12, 18, and 24 months
TTV virus (Anellovirus) load in plasma at 0, 4, 8, 20 weeks, and 6, 12, 18, and 24 months
Markers of complement activation and strength in plasma and urine at 0, 4, 8, 20 weeks, and 6, 12, 18, and 24 months, in relation to a genetic analysis of the C4 gene and genes of other essential complement proteins

E.5.2.1

Timepoint(s) of evaluation of this end point

0-24 months after randomization

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

This study will be monitored by an independent data and safety monitoring board (DSMB) of the Medical University of Vienna (MUW). An interim analysis will be performed by the DSMB after 10 and 20 cases in the treatment group are completed. The Lan & DeMets extension of the O’Brian-Fleming stopping rules will be applied. The trial will be stopped if the observed p-value are <0.00001 and <0.00305, respectively.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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

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)

no posttreatment plans

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

2013-07-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-01-23

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