Clinical Trials Register

Summary
EudraCT Number:	2007-005503-17
Sponsor's Protocol Code Number:	200710602
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2007-10-30
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

Germany - PEI

A.2

EudraCT number

2007-005503-17

A.3

Full title of the trial

Randomized multicenter double-blind study of phase III in patients after kidney transplantation with an acute cellular rejection with a tubulointerstinal component in kidney transplant with histologic proof of an infiltrate with CD20-positive Lymphocytes in proof of the superiority of a therapy with Steroidboli plus Rituximab/MabThera® in comparison to a solitary therapy with Steroidboli with regard to kidney function after one year.

Randomisierte multizentrische Doppelblindstudie der Phase III bei Patienten nach Nierentransplantation mit einer akuten zellulären Rejektion mit tubulointerstitieller Komponente im Nierentransplantat mit CD20-positiven Lymphozyten zum Nachweis der Überlegenheit einer Therapie mit Steroidboli plus Rituximab/MabThera® im Vergleich zu einer alleinigen Therapie mit Steroidboli bezüglich der Nierenfunktion nach einem Jahr

A.3.1

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

Patients after a kidney transplantation with an acute cellular rejection in kidney transplant, to proof the superiority of a therapy with Steroidboli plus Rituximab/MabThera® in comparison to a solitary therapy with Steroidboli with regard to kidney function after one year.

Patienten nach einer Nierentransplantation mit einer akuten Abstoßungsreaktion, welche mit Steroiden und Rituximab/MabThera® im Vergleich mit Steroiden allein bezüglich der Nierenfunktion behandelt werden.

A.3.2

Name or abbreviated title of the trial where available

RIACT

A.4.1

Sponsor's protocol code number

200710602

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	Medizinische Hochschule Hannover
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	Bundesministerium für Bildung und Forschung (BMBF)
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medizinische Hochschule Hannover, Studienzentrum für Nieren- und Hochdruckerkrankungen
B.5.2	Functional name of contact point	Studienzentrum
B.5.3	Address:
B.5.3.1	Street Address	Stadtfelddamm 65
B.5.3.2	Town/ city	Hannover
B.5.3.3	Post code	30625
B.5.3.4	Country	Germany
B.5.4	Telephone number	+495115323000
B.5.5	Fax number	+495115329358
B.5.6	E-mail	studienzentrum@mh-hannover.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	MabThera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
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	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	MabThera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
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	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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 infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

It should be proved that additional treatment with Rituximab in patients with histologic proof of an acute cellular rejection with CD20+ lymphocytes is superior to a solitary therapy with Steroidboli with regard to kidney function after one year.

Es soll nachgewiesen werden, dass eine zusätzliche Behandlung mit Rituximab bei Patienten mit histologischem Nachweis einer akuten zellulären Abstoßung mit CD20+ Lymphozyten einer alleinigen Therapie mit Steroidboli im Hinblick auf die Nierenfunktion nach einem Jahr überlegen ist.

E.1.1.1

Medical condition in easily understood language

It should be proved that additional treatment with Rituximab in patients with histologic proof of an acute cellular rejection is superior to a solitary therapy with Steroidboli.

Nachweis, dass eine zusätzliche Behandlung mit dem Medikament Rituximab bei Patienten mit einer akuten Abstoßung einer alleinigen Therapie mit Steroiden überlegen ist.

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10023439
E.1.2	Term	Kidney transplant rejection
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Es soll nachgewiesen werden, dass eine zusätzliche Behandlung mit Rituximab bei Patienten mit histologischem Nachweis einer akuten zellulären Abstoßungsreaktion mit CD 20-positiven Lymphozyten einer alleinigen Therapie mit Steroidboli im Hinblick auf die Langzeit-Nierenfunktion nach einem Jahr überlegen ist.

E.2.2

Secondary objectives of the trial

n/a

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion:
1.male or female patients age ≥ 18 at the time of the inclusion in the study
2.Kidney transplantation <= 24 months ago
3.Proof of an acute cellular tubulointerstitial rejection in kidney transplant using Banff-criteria (grade IA/B or IIA/B (no v-only)) or Banff Borderline Rejection, which has to be treated with steroidtheraphie in the opinion of the investigator with an infiltrate with CD 20+ lymphocytes (≥20 /visual field), that are detected in the course of a protocol biopsy or an indication biopsy.
4.C4d- and SV40-negativity in the biopsy
5.GFR according to MDRD-Formula > 25 ml/min/1,73 m² in the time period before the noticed rejection
6.Presence of a negative pregnancy test and consent to a highly effective contraceptiive method (i.e. failure rate less than 1% per year, which are implants, injectable contraceptives, combined oral contraceptives, intrauterine devices (only hormone spirals), sexual abstinence or vasectomy of the partner) in patients of child-bearing age. This does not apply to bilateral ovariectomy or sterilization of the patient and in patients that have exclusively female sex partners.
7.Informed Consent

1. männliche oder weibliche Patienten im Alter ≥ 18 Jahre zum Zeitpunkt des Studieneinschluss
2. Nierentransplantation vor <= 24 Monaten
3. Nachweis einer akuten zellulären tubulointerstitiellen Rejektion im Nierentransplantat nach Banff-Kriterien (Grad IA/B oder IIA/B (keine v-only)) oder Banff Borderline Rejektion, die nach medizinisch-ärztlicher Einschätzung mit Steroidtherapie behandelt werden soll, mit einem Infiltrat mit CD 20+ Lymphozyten (≥20 /Gesichtsfeld), die im Rahmen einer Protokoll- oder einer Indikationsbiopsie entdeckt werden.
4.C4d- und SV40-Negativität in der Biopsie
5.GFR nach MDRD-Formel > 25 ml/min/1.73 m² im Zeitraum vor der festgestellten Rejektion.
6.Bei Patientinnen im gebärfähigen Alter Vorliegen eines negativen Schwangerschaftstest und Einverständnis zu einer hoch effektiven Methode der Kontrazeption (d.h. mit einer Versagerquote von weniger als 1 % pro Jahr, dies sind Implantate, Injektionspräparate, kombinierte orale Kontrazeptiva, Intrauterinpessare (nur Hormonspiralen), sexuelle Abstinenz oder Vasektomie des Partners). Dieses entfällt bei beidseitiger Sterilisation oder Ovarektomie der Patientin und bei Patientinnen, die ausschließlich weibliche Sexualpartnerinnen haben
7. Schriftliche Einverständniserklärung

E.4

Principal exclusion criteria

Exclusion:
1.Known contraindications, resp. incompatibility for Rituximab resp. for the concomitant medication
2.Administration of Rituximab within the last 24 months before inclusion
3.Simultaneous participation in an other clinical study (observational studies and register excluded)
4.Breastfeeding women or pregnant women
5.Persons who fail to assess essence, meaning and significance of the clinical study and act along these lines (according to § 40 Abs. 4 und § 41 Abs. 2 und Abs. 3 AMG)
6.Existence of an active CMV-infection, existence of a HIV-infection, existence of a replicative hepatitis B or C, existence of other grave infections
7.Cardiac insufficiency in phase NYHA III-IV
8.High grade cardiac arrhythmias
9.Unstable coronary heart disease
10.Poorly adjusted diabetes mellitus at the time of the inclusion in the study.
11.State after splenectomy
12.Contra-indication referring to a renewed transplant biopsy (e.g. coagulopathy, anticoagulation)
13.Other exclusion criteria according to the estimate of the attending doctor (e.g. aggravation of the general health condition, occurrence of a malignant disease)

1. Bekannte Gegenanzeigen, bzw. Unverträglichkeit für Rituximab bzw. für die Begleitmedikation
2. Gabe von Rituximab innerhalb von 24 Monaten vor Studieneinschluss
3.Gleichzeitige Teilnahme an einer anderen klinischen Prüfung (hierzu zählen nicht Anwendungsbeobachtungen und Register)
4. Stillende Frauen oder Schwangere
5. Personen, die nicht in der Lage sind, Wesen, Bedeutung und Tragweite der klinischen Prüfung zu erkennen und ihren Willen hiernach auszurichten (gemäß § 40 Abs. 4 und § 41 Abs. 2 und Abs. 3 AMG)
6. Vorliegen eines aktiven CMV-Infektes, Vorliegen einer HIV-Infektion, Vorliegen einer replikativen Hepatitis B oder C, Vorliegen sonstiger schwerer Infektionen
7. Herzinsuffizienz im Stadium NYHA III-IV
8. Höhergradige Herzrhythmusstörungen
9. Instabile Koronare Herzkrankheit
10. Schlecht eingestellter Diabetes mellitus zum Zeitpunkt des Einschluss in die Studie
11. Zustand nach Splenektomie
12. Kontraindikation bezüglich einer erneuten Transplantatbiopsie (z.B. Gerinnungsstörung, Antikoagula-tion)
13. Andere Ausschlusskriterien nach Einschätzung des behandelnden Arztes (z.B. Verschlechterung des Allgemeinzustandes, Auftreten einer malignen Erkrankung)

E.5 End points

E.5.1

Primary end point(s)

Change in the GFR one year after rejection treatment in comparison to a baseline GFR for the state before the rejection detected by a principal investigator at the time of the randomization

Primärer Endpunkt soll die ΔGFR sein, berechnet aus einem Baseline-Kreatininwert vor der festgestellten akuten Rejektion und dem Kreatininwert ein Jahr nach Behandlung mit Rituximab bzw. Placebo.

E.5.1.1

Timepoint(s) of evaluation of this end point

one year after treatment

Ein Jahr nach Behandlung

E.5.2

Secondary end point(s)

n/a

E.5.2.1

Timepoint(s) of evaluation of this end point

n/a

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

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

n/a

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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:

126

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

180

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)

standard care

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-03-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-02-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-05-02

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