Clinical Trials Register

Summary
EudraCT Number:	2012-004915-30
Sponsor's Protocol Code Number:	HO113
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-04-11
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

Italy - Italian Medicines Agency

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.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.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	HOVON Data Center
B.5.2	Functional name of contact point	HDC
B.5.3	Address:
B.5.3.1	Street Address	's-Gravendijkwal 230
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015 CE
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31(0)107041560
B.5.5	Fax number	+31(0)107041028
B.5.6	E-mail	hdc@erasmusmc.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.3.11 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	16.1
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	16.1
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 second line treatment
• 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 develop a score by means of clinical and laboratory parameters that allows for identification of patients with acute GvHD that will respond to 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);
• Non-responsive to treatment with steroids and a calcineurin-inhibitor defined as:
- progressive disease of mixed response after 5 days of consecutive systemic treatment with steroids at a dose of 2 mg/kg and a calcineurin-inhibitor at therapeutic trough levels.
- stage 4 GvHD of gut and/or liver and deterioration of clinical parameters (gut) or increase of serum total bilirubin levels in micromol/L (liver) after 5 days of consecutive systemic treatment with steroids at a dose of 2 mg/kg and a calcineurin-inhibitor at therapeutic trough levels
- stable disease after 10 days of consecutive systemic treatment with steroids at a dose of 2 mg/kg and a calcineurin-inhibitor at therapeutic trough levels.
- progressive disease after initial partial repsons of maximal 1 grade after 10 days of consecutive systemic treatment with steroids at a dose of 2 mg/kg 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 prophylactic MMF, Myfortic or other systemic treatment for acute GvHD <= 6 days prior to development of acute GvHD grade II-IV with gut and/or liver involvement.
• Systemic treatment for acute GvHD other than steroids and a calcineurin inhibitor (budesonide is considered a local treatment).
• Previous treatment with MSC.
• 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 seropositivity of HIV, Hepatitis B and C, HTLV.
• Known uncontrolled toxicity for DMSO.
• Known anaphylactic reaction to penicillin or streptomycin;
• Known pregnancy;
• 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 responding to treatment of acute GvHD grade II-IV (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)

- Overall Survival
- Progression-free survival
- Duration of acute GvHD response
- Time without systemic immunosuppression.
- Cumulative incidence of non-relapse mortality
- Adverse events
- Incidence of chronic GvHD
- Quality of life
- Immununological monitoring including monitoring of absolute T-cell subsets, B-cells, NK-cells as well as biomarkers of acute GvHD

E.5.2.1

Timepoint(s) of evaluation of this end point

An interim analysis will take place when 50% of the patients are included. These results will be reviewed confidentially by the DSMB.
Final analysis will take place when the relevant data of all patients are available

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

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

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

2016-11-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-30

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

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