Clinical Trials Register

Summary
EudraCT Number:	2008-005862-30
Sponsor's Protocol Code Number:	MHH-Pre-GvHD-001
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-12-15
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 - BfArM

A.2

EudraCT number

2008-005862-30

A.3

Full title of the trial

Pre-emptive therapy of acute graft versus host disease according to specific proteomic patterns after allogeneic hematopoietic stem cell transplantation.

A.3.1

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

Early therapy of acute bone marrow rejection according to specific proteins detected in urine after bone marrow transplantation.

A.3.2

Name or abbreviated title of the trial where available

PRE-GvHD

A.4.1

Sponsor's protocol code number

MHH-Pre-GvHD-001

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
B.5.2	Functional name of contact point	Prof. Dr. Eva Mischak-Weissinger
B.5.3	Address:
B.5.3.1	Street Address	Carl-Neuberg-Str. 1
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	+495115329518
B.5.5	Fax number	+495115326843
B.5.6	E-mail	Mischak-Weissinger.Eva@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.2.1.2	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.3.1	Product name	Prednisolone
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PREDNISOLONE
D.3.9.1	CAS number	2920867
D.3.9.3	Other descriptive name	PREDNISOLONE HYDROGEN SUCCINATE
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.2.1.2	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.3.1	Product name	Prednisolone
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	PREDNISOLONE
D.3.9.1	CAS number	50248
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	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	Tablet
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

Pre-emptive therapy of acute graft versus host disease with prednisolone according to specific proteomic patterns after allogeneic hematopoietic stem cell transplantation.

E.1.1.1

Medical condition in easily understood language

Early Prednisolone therapy of acute bone marrow rejection according to specific proteins detected in urine after bone marrow transplantation.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10018652
E.1.2	Term	Graft versus host reaction
E.1.2	System Organ Class	100000004870

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 test the efficacy of pre-emptive immunosuppressive treatment (2-2.5mg prednisolone/kg BW/day) versus placebo immediately when a positive acute Graft-versus-Host disease (aGvHD,grade II-IV) and a specific proteomic pattern is observed.

E.2.2

Secondary objectives of the trial

To test the efficacy of pre-emptive treatment of (1) severity of aGvHD, (2) allogeneic HSCT related mortality due to toxicitiy or infections, (3) overall survival, (4) incidence of leukemic relapses and (5) safety of pre-emptive treatment

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Written informed consent
• All patients ≥ 18 years on day +7 (+/- 3) after 1st allo-HSCT
• Patients transplanted for: acute myeloid or lymphoid leukemia in CR (<5% leukemic blast cells in the bone marrow) or PR (<20% leukemic blast cells in the bone marrow); myelodysplastic and/or myeloproliferative syndromes: untreated, CR, PR; lymphomas: PR; chronic myeloid leukemia: CP; chronic lymphatic leukemia: CR, PR; multiple myeloma: CR, PR; severe aplastic anemia at the time of allogeneic HSCT
• aGvHD prophylaxis with any combination of the following: e.g. cyclosporin A (CsA), methotrexate (MTX), mycophenolic acid (MMF), tacrolimus, sirolimus, everolimus and others with or with-out immunosuppressive antibodies (e.g. anti-thymocyte globulin (ATG))
• Woman of childbearing potential must have a negative pregnancy test prior to HSCT
• Sufficient contraceptive methods for men and women of reproductive age at the beginning of the study and during the study and consent of the patient to used a sufficient contraceptive method within 6 months after the end of the study. Permitted double contraceptive methods are implants, injection preparation, intrauterine devices, portal cap, sterilization, hysterectomy, condoms, spermicide, vasectomy and/or sexual abstinence.

Prior to randomization:
• Positivity of aGvHD-specific proteomic pattern

(Patients enrolled, who can not be randomized, will be followed-up in the observational group).

E.4

Principal exclusion criteria

• Patients after ≥ 2nd allo-HSCT
• Patients transplanted in relapse of their underlying disease (AML, ALL: ≥20% leukemic blast cells in the bone marrow)
• Transplantation with CD34+-enriched or ex vivo T-cell-depleted stem cells, transplantation from syngeneic or haploidentical or cord blood donors
• Steroids as part of the acute GvHD prophylaxis
• Pregnant or nursing women
• Participation in an other therapeutic study within 30 days before and during this study

Prior to randomization:
• Patients with acute GvHD grade II to IV
• Acute renal failure (≥ 2x upper normal boundary of serum creatinine)
• Serious, life-threatening infection at the time of sampling for aGvHD proteomic pattern
• Relapse or progression of underlying disease

(Patients enrolled, who cannot be randomized, will be followed-up in the observational group).

E.5 End points

E.5.1

Primary end point(s)

Primary study endpoint:
Occurrence of aGvHD (≥ grade II) between time of randomization and 100 days after allo-HSCT. Death occurring between randomization and 100 days post allo-HSCT without aGvHD (≥ grade II) will be considered as treatment failure, equivalent to an aGvHD (≥ grade II) development.

E.5.1.1

Timepoint(s) of evaluation of this end point

100 days after allo-HSCT

E.5.2

Secondary end point(s)

Secondary study endpoints:
(1) Severity of aGvHD until day 100 after allo-HSCT, (2) all aGvHD (≥ grade II), (3) severity of all aGvHD, (4) transplant-related mortality (TRM), (5) overall survival, (6) occurrence of leukemic relapses and (7) infectious complications.

Additional scientific endpoints:
To establish proteomic patterns specific for steroid-resistant aGvHD.

E.5.2.1

Timepoint(s) of evaluation of this end point

(1) until 100 days after allo-HSCT
(2)-(6) until end of follow-up period (100 days + 365 days)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

Yes

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)

Yes

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

Information not present in EudraCT

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 (normal)

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:

234

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

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)

Patients get the standard treatment which belongs to the allo-HSCT

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

2009-01-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-02-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-12-07

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