Clinical Trials Register

Summary
EudraCT Number:	2012-004915-30
Sponsor's Protocol Code Number:	HO113
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-01-30
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

Netherlands - Competent Authority

A.2

EudraCT number

2012-004915-30

A.3

Full title of the trial

Treatment of severe steroid-refractory acute GvHD with mesenchymal stromal cells.
A phase III, randomized double-blind multi-center HOVON study.

Behandeling van ernstige steroïde-ongevoelige acute GvHZ met mesenchymale stromale cellen. Een fase III gerandomiseerde dubbelblinde multi-center HOVON studie.

A.3.1

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

Treatment of severe steroid-refractory acute GvHD with mesenchymal stromal cells.

Behandeling van ernstige steroïde-ongevoelige acute GvHZ met mesenchymale stromale cellen.

A.3.2

Name or abbreviated title of the trial where available

HOVON 113 MSC

A.4.1

Sponsor's protocol code number

HO113

A.5.4

Other Identifiers

Name:

NL42497.000.12

Number:

NTR4227

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	HOVON Foundation
B.1.3.4	Country	Netherlands
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	Dutch Cancer Society
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Sanquin Blood Supply
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	European Union Horizon2020 Grant Agreement Nr 643580
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Principal Investigator
B.5.2	Functional name of contact point	W.E. Fibbe
B.5.3	Address:
B.5.3.1	Street Address	Albinusdreef 2
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 ZA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31(0)715263800
B.5.5	Fax number	n.a.n.a.n.a.
B.5.6	E-mail	w.e.fibbe@lumc.nl

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	mesenchymal stromal cells
D.3.4	Pharmaceutical form	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	Bone marrow derived ex vivo expanded cryopreserved MSCs
D.3.9.1	CAS number	n.a.
D.3.9.2	Current sponsor code	n.a.
D.3.9.3	Other descriptive name	EX VIVO CULTURED HUMAN MESENCHYMAL STEM CELLS
D.3.9.4	EV Substance Code	SUB27304
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	1000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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 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

Graft Versus Host Disease

E.1.1.1

Medical condition in easily understood language

Graft Versus Host Disease

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10066260
E.1.2	Term	Acute graft versus host disease
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10068908
E.1.2	Term	AGVHD
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To improve the response rate to treatment of acute GvHD grade II-IV (with gut and/or liver involvement) by early addition of MSC to standardized second line treatment.

E.2.2

Secondary objectives of the trial

• To study the safety of MSC addition to standardized second line treatment
• To assess the incidence of treatment-related mortality
• To assess the overall survival
• To assess the progression-free survival
• To reduce the time required for continued pharmacological immune suppression
• To assess the incidence of severe bacterial, viral and fungal infections
• To assess the incidence and severity of chronic GvHD
• To evaluate the quality of life of patients treated with MSC in comparison with controls up to two years after MSC treatment
• To establish the economic impact of MSC for the treatment of severe steroid-refractory acute GvHD (with gut and/or liver involvement)
• To develop a score by means of clinical and laboratory parameters that allows for identification of patients with severe acute GvHD that will respond on MSC treatment

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Grade II-IV acute GvHD with gut and/or liver involvement, confirmed by histology of involved tissues (in case of gut and liver involvement histology of either one of these tissues is considered sufficient); N.B. if histological confirmation at randomization is lacking or inconclusive but the patient is otherwise eligible and acute GvHd is considered the most likely cause of the symptoms, the patient may be included but histology of involved tissue (if lacking) should still be obtained as soon as deemed feasible and/or safe
• Steroid-refractory defined as progressive disease, mixed response, or grade IV disease after at least 5 days, or stable grade II-III disease after at least 7 days of consecutive systemic treatment with steroids at a dose of ≥ 2 mg/kg prednisolone or steroid equivalent and a calcineurin-inhibitor at therapeutic trough levels
• Any age;
• Lansky / Karnofsky score of ≥20;
• Signed informed consent by the patient and/or parent(s) or legal guardian(s).

E.4

Principal exclusion criteria

• Use of intravenous prophylactic MMF ≤ 6 days prior to development of acute GvHD ;
• Systemic treatment for acute GvHD other than steroids and a calcineurin inhibitor (budesonide is considered a local treatment);
• Consecutive treatment with steroids ≥ 2 mg/kg prednisolone or steroid equivalent > 10 days directly prior to inclusion;
• Previous treatment with advanced therapy medicinal products (ATMP) potentially interfering with the endpoints of this study;
N.B. if there is doubt regarding potential interference, the principal investigator should always be contacted prior to registration*.
• Known progressive or relapsing malignant disease in case of NHL, HL, CLL, MM, and ≥ 5% blasts in the bone marrow in case of AML, ALL, CML;
• Requiring ventilator or vasopressor support;
• Poor performance not expected to survive 14 days;
• Known uncontrolled hypersensitivity to DMSO;
• History of any other malignancy, unless diagnosed and treated > 5 years ago with curative intent and without recurrence or nonmelanoma skin cancer and/or carcinoma in situ of any type following complete resection.
• Known pregnancy, a positive highly sensitive pregnancy test at screening, or lactation for female patients; unwillingness to practice highly effective means of contraception for both female and male patients of reproductive potential, as described in paragraph 9.4;
• Any psychological, familial, sociological and /or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with complete or partial response to treatment of acute GvHD grade II-IV with (with gut and/or liver involvement) at day 29.

E.5.1.1

Timepoint(s) of evaluation of this end point

Two interim analyses will take place after inclusion of 33% and 67% of patients.
These results will be reviewed confidentially by the DSMB.
Final analysis will take place when the relevant data of all patients are available.

E.5.2

Secondary end point(s)

• Cumulative incidence of treatment-related mortality, defined as death not due to relapse of hematological malignancy (non-relapse mortality), at 6 months and beyond
• Overall survival, defined as time from randomization until death from any cause. Patients alive at the date of last contact will be censored
• Progression-free survival, defined as time from randomization until progression or relapse of hematological malignancy or death, whichever comes first
• Duration of acute GvHD response, defined as time from response of acute GvHD until relapse of acute GvHD or death, whichever comes first
• Time from end of systemic immunosuppressive treatment for GvHD until re-initiation of systemic immunosuppression for GvHD
• Adverse events
• Incidence of chronic GvHD
• Quality of life
• Immunological monitoring including monitoring of absolute numbers of all T-cell subsets, B-cells, and NK-cells as well as biomarkers of acute GvHD

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

125

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Inclusion criteria is any age. Children with GVHD can be entered in the trial with parents/legal guardians consent.

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

150

F.4.2.2

In the whole clinical trial

150

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)

Treatment after end of protocol treatment is at the discretion of the treating physician. For children, this may include MSC treatment.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	HOVON Foundation
G.4.3.4	Network Country	Netherlands

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-01-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-05

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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