Clinical Trials Register

Summary
EudraCT Number:	2017-001604-30
Sponsor's Protocol Code Number:	1001
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-02-06
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

2017-001604-30

A.3

Full title of the trial

Safety, Tolerability and Efficacy of anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Rejection after Kidney Transplantation - A Pilot Trial

Sicherheit, Verträglichkeit und Aktivität des anti-IL-6 Antikörpers Clazakizumab bei später Antikörper-mediierter Abstoßung nach Nierentransplantation - eine Pilotstudie

A.3.1

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

Safety, Tolerability and Efficacy of an antibody, which blocks the pro-inflammatory mediator Interleukin-6, in patients with late Antibody-mediated rejection of a transplanted kidney - A Pilot Trial

Sicherheit, Verträglichkeit und Effektivität von Clazakizumab, einem Antikörper, welcher das entzündungsfördernde Interleukin-6 blockiert, in Patienten mit später, Antikörper vermittelter Abstoßung eines Nierentransplantats - eine Pilotstudie

A.4.1

Sponsor's protocol code number

1001

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 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	Charité Berlin
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	PSST
B.5.2	Functional name of contact point	consultancy
B.5.3	Address:
B.5.3.1	Street Address	Kreillerstr 65
B.5.3.2	Town/ city	Muenchen
B.5.3.3	Post code	81673
B.5.3.4	Country	Germany
B.5.4	Telephone number	+498992200350
B.5.5	Fax number	+4932127778833
B.5.6	E-mail	axel.wenzel@p-ss-t.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	No
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	Clazakizumab
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLAZAKIZUMAB
D.3.9.1	CAS number	1236278-28-6
D.3.9.2	Current sponsor code	CLAZAKIZUMAB
D.3.9.3	Other descriptive name	CLAZAKIZUMAB
D.3.9.4	EV Substance Code	SUB117542
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	25
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	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	Isotonische Kochsalzlösung Fresenius Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Kabi Deutschland GmbH
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
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous 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
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
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Antibody-mediated rejection of a kidney transplant

E.1.1.1

Medical condition in easily understood language

Patients who received a kidney transplantation and the transplant is now rejected. The rejection is mediated by specific antibodies. This needs to be established in blood and biopsy investigations.

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

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 investigate safety and tolerability of Interleukin-6 blockade by clazakizumab in kidney transplant recipients on baseline immunosuppresion.

E.2.2

Secondary objectives of the trial

- To investigate the pharmacokinetics and pharmacodynamics of clazakizumab
- To investigate the effects of IL-6 blockade on Antibody-mediated rejection (ABMR) biomarkers: Donor specific antigen mean fluorescence intensity, serum markers of inflammation and endothelial injury
- To investigate the effects of IL-6 blockade on biopsy results, microcirculation, inflammation, chronic injury and gene expression
- To investigate the effects of IL-6 blockade on kidney function parameters (eGFR, urinary protein, cytokine measurements)
- To investigate the effects of IL-6 blockade on cytochrome dependent drug metabolism
- To investigate the effects of IL-6 blockade on leukocyte subpopulations
- To investigate the effects of IL-6 blockade on Torque Teno Viremia

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Voluntary written informed consent
- Age >18 years
- functioning living or deceased donor allograft >365 days post-transplantation
- eGFR>30ml/min/1.73m2
- Detection of HLA class I and/or II antigen-specific antibodies (preformed and/or de novo DSA)
- Acute/active or chronic/active ABMR (±C4d in PTC) according to BANFF 2013/2015
- Molecular ABMR score (ABMRpm) ≥0.2

E.4

Principal exclusion criteria

- active participation in another clinical trial
- age <18 years
- female subject is pregnant or lactating
- index biopsy results:
*T-cell medated rejection classified BANFF grade ≥ I
*de novo or recurrent severe thrombotic microangiopathy
*Polyoma virus nephropathy
* de novo or recurrrent glomerulonephritis
- acute rejection treatment <3 months before screening
- acute deterioration of graft function (eGFR decline within 1-3 months >25%)
- nephrotic range proteinuria >3500mg/g protein/creatinine ratio
- Active vrial, bacterial or fungal infection precluding intensified immunosuppression
- Active malignant disease precluding intensified immunosuppression
- Abnormal liver function tests (ALT, AST, bilirubin >1.5x upper limit of normal)
- Other significant liver disease
- latent or active tuberculosis (positive QuantiFERON- TB GOD test, Chest X-Ray)
- Administration of a live vaccine within 6 weeks of screening
- neutropenia (<1 G/L) or thrombocytopenia (<100 G/L)
- history of gastrointestinal perforation, diverticulitis, or inflammatory bowel disease
- history of alcohol or illicit substance abuse
- serious medical or psychiatric illness likely to interfere with participation in the study

E.5 End points

E.5.1

Primary end point(s)

- Safety and Tolerability of Clazakizumab

E.5.1.1

Timepoint(s) of evaluation of this end point

Part A: Weeks 12
Part B: Week 52

E.5.2

Secondary end point(s)

- PK of clazakizumab (every visit; measurement of anti-Claza antibodies included) and of pantoprazole (0, 12, 52 weeks)
- PD of clazakizumab (CRP suppression) (every visit)
- Cytokines patterns and endothelial activation/injury markers in serum (0, 12, 52 weeks)
- Effect on leukocyte subsets in peripheral blood
- Effect on IL-6 and IL-6R gene expression in peripheral blood cells
- HLA antibody levels (0, 12, 52 weeks)
Maximum and sum of mean fluorescence intensity (MFI) of DSA
Number of DSA
Broadness of sensitization (virtual PRA)
- Total Ig classes (IgG, IgA, IgM) and IgG subclasses (IgG1, 2, 3, 4)
- Protocol biopsy results at 11 and 51 weeks
ABMR category
Microcirculation inflammation (g+ptc score)
Transplant glomerulopathy (cg) and interstitial fibrosis/tubular atrophy (IFTA) scores
Molecular ABMR score (molecular microscope, MMDx)
Archetype analysis of gene expression profiles (molecular microscope, MMDx)
- eGFR (every visit)
- Protein excretion (protein/creatinine ratio) (every visit)
- 1-year graft and patient survival
- Occurrence of biopsy-proven acute rejection necessitating rejection treatment (52 weeks)

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 0, 12 and 52 (as applicable for each study part)

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

Yes

E.6.7

Pharmacodynamic

Yes

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

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

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)

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

The post trial treatment will be performed by the Department of Nephrology at the Medical University of Vienna, or the Charite Berlin as applicable. This could also involve further treatment with Interleukin-6 inhibitors, if required.

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

2018-05-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-09-04

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