Clinical Trials Register

Summary
EudraCT Number:	2013-005508-33
Sponsor's Protocol Code Number:	MC-FludT.16/NM
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-08-08
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2013-005508-33

A.3

Full title of the trial

Clinical phase II trial to compare Treosulfan-based conditioning therapy with Busulfan-based conditioning prior to allogeneic haematopoietic stem cell transplantation (HSCT) in paediatric patients with non-malignant diseases

A.3.1

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

Comparison of Treosulfan-based with Busulfan-based conditioning in paediatric patients with non-malignant diseases

A.3.2

Name or abbreviated title of the trial where available

Treosulfan-based versus Busulfan-based conditioning in paediatric patients with non-malignant diseas

A.4.1

Sponsor's protocol code number

MC-FludT.16/NM

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/346/2020

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	medac GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	medac GmbH
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	Syneos Health UK Limited
B.5.2	Functional name of contact point	Shaista Hussain
B.5.3	Address:
B.5.3.1	Street Address	Farnborough Business Park, 1 Pinehurst Road,
B.5.3.2	Town/ city	Farnborough, Hampshire,
B.5.3.3	Post code	GU14 7BF
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0031 1207528717
B.5.6	E-mail	shaista.hussain@syneoshealth.com

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	Ovastat 1000 (Treosulfan injection)
D.2.1.1.2	Name of the Marketing Authorisation holder	medac 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	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/186
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder 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	TREOSULFAN
D.3.9.1	CAS number	299-75-2
D.3.9.4	EV Substance Code	SUB11235MIG
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	1000
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.2.1.1.1	Trade name	Ovastat 5000 (Treosulfan injection)
D.2.1.1.2	Name of the Marketing Authorisation holder	medac 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	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/186
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder 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	TREOSULFAN
D.3.9.1	CAS number	299-75-2
D.3.9.4	EV Substance Code	SUB11235MIG
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	5000
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: 3
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	Busilvex
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre Medicament
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/00/011
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	BUSULFAN
D.3.9.1	CAS number	55-98-1
D.3.9.4	EV Substance Code	SUB05993MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Male and female children with non-malignant diseases requiring myeloablative conditioning treatment with following allogeneic haematopoietic stem cell transplantation (allo-HSCT) – i.e. primary immunodeficiencies, inborn errors of metabolism, haemoglobinopathies and bone marrow failure syndromes.

E.1.1.1

Medical condition in easily understood language

Children with non-malignant diseases requiring conditioning treatment prior to stem cell transplantation

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10021606
E.1.2	Term	Inborn errors of metabolism NEC
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10036700
E.1.2	Term	Primary immunodeficiency syndromes
E.1.2	System Organ Class	100000004870

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10018903
E.1.2	Term	Haemoglobinopathies congenital
E.1.2	System Organ Class	100000004850

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

Comparative evaluation of freedom from transplant (treatment)-related
mortality (TRM), defined as death from any transplant-related cause
from start of conditioning treatment (day -7) until day +100 after HSCT.

E.2.2

Secondary objectives of the trial

Comparative evaluation of:
1. Neutropihil and platelet engraftment after HSCT.
2. Safety including early toxicity (defined as toxicities occurring until day
+28), until day +100 after HSCT, SARs until the end of longer-term
follow-up phase.
3. HSOS, lung toxicity, hepatic toxicity and infections of any CTCAE grade
until day +100.
4. Chimerism on day +28, day +100 and 12 months after HSCT.
5. OS until 12 months after HSCT.
6. Graft failure until 12 months after HSCT.
7. Acute (until day +100) and chronic (until 12 months after HSCT)
GvHD.
8. Use of rescue therapies including DLIs, stem cell infusions with or
without further conditioning regimens, re-occurrence of transfusion
dependence (i.e. necessity of regular transfusions of red blood cells or
platelets.
9. PK parameters of Treosulfan and its epoxides and to develop a PK
model for assessing relevant covariates.
10. Graft failure, cGvHD, donor-type chimerism, OS and TRM during the
longer-term follow-up phase.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Non-malignant disease indicated for first myeloablative allogeneic
HSCT, including inborn errors of metabolism, primary
immunodeficiencies, haemoglobinopathies and bone marrow failure
syndromes.
2. First allogeneic HSCT.
3. Available matched sibling donor (MSD), matched family donor (MFD)
or matched unrelated donor (MUD). For bone marrow (BM) and
peripheral blood (PB) match is defined as at least 9/10 allele matches
after four digit typing in human leucocyte antigen (HLA)-A, -B, -C, –
DRB1 and DQB1 antigens. For umbilical cord blood (UCB) match is
defined as at least 5/6 matches after two digit typing in HLA-A and -B
and four digit typing in DRB1 antigens.
4. Age at time of registration from 28 days to less than 18 years of age.
5. Lansky (patients <16 years of age) or Karnofsky (patients ≥ 16 years
of age) performance score of at least 70%.
6. Written informed consent of the parents/legal guardians and patient's
assent/consent according to national regulations.
7. Female patients of child-bearing potential or partner of male patients
with child-bearing potential must use a highly effective method of
contraception (pearl index < 1%) such as complete sexual abstinence,
combined oral contraceptive, hormone intrauterine contraceptive device
(IUCD), vaginal hormone ring, transdermal contraceptive patch,
contraceptive implant or depot contraceptive injection in combination
with a second method of contraception like a condom or a cervical cap /
diaphragm with spermicide or surgical sterilisation (vasectomy) in male
patients or male partners during the study and at least six months
thereafter. For female patients on the study, the vasectomized male partner should be the sole partner for this patient.
8. Negative pregnancy test for females of child-bearing potential.

E.4

Principal exclusion criteria

1. Second or later HSCT.
2. HSCT from mismatched donor (less than 9/10 BM/peripheral blood
stem cells (PBSC) or less than 5/6 matched cord donor).
3. Preterm newborn infants (<37 weeks gestational age) and term
newborn infants aged 0 – 27 days at time of registration.
4. Obese paediatric patients with body mass index weight (kg)/[height
(m)]² > 30 kg/m².
5. Diagnosis of Fanconi anaemia and other chromosomal breakage
disorders, radiosensitivity disorders (deoxyribonucleic acid (DNA) Ligase
4, Cernunnos- X-ray repair cross-complementing protein 4 (XRCC4) like
factor (XLF), Nijmegen Breakage Syndrome (NBS)) and Dyskeratosis
Congenita.
6. Treatment with cytotoxic drugs within 10 days prior to day 7.
7. Impaired liver function indicated by Bilirubin > three times the upper
limit of normal (ULN) or aspartate aminotransferase/alanine
aminotransferase (AST/GOT, ALT/GPT) > ten times ULN or clinically significant coagulopathy, or active
infectious hepatitis with clinical evidence.
8. Impaired renal function indicated by estimated glomerular filtration
rate ([GFR], according to the Schwartz formula) < 60 mL/min/1.73m2.
9. Impaired cardiac function: severe cardiac insufficiency indicated by
left ventricular ejection fraction (LVEF)  35%.
10. Requirement for supplementary continuous oxygen.
11. Severe active infection requiring deferral of conditioning.
12. Human immunodeficiency virus (HIV) positivity.
13. Severe concomitant illness, comorbidity or condition that would
severely limit life expectancy.
14. Known pregnancy, breast feeding.
15. Known hypersensitivity to Treosulfan, Busulfan, Fludarabine and/or
Thiotepa.
16. Participation in another interventional clinical study with an
experimental drug, within four weeks prior to patient inclusion.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

Day +100 after HSCT

E.5.2

Secondary end point(s)

1. Comparative evaluation of engraftment after HSCT, defined as the first
of three consecutive days for each of the following four criteria:
- a leukocyte count of more than 1 x 109/L
- an absolute neutrophil count (ANC) of more than
0.5 x109/L
- a platelet count of at least 20 x109/L
- a platelet count of at least 50 x109/L.
2. Comparative evaluation of safety including early toxicity (defined as
toxicities occurring until day +28), based on Common Terminology
Criteria for Adverse Events (CTCAE) version 4.03 until day +100 after
HSCT, serious adverse reactions (SARs) until the end of longer-term
follow-up phase (three years after HSCT of last patient).
3. Comparative evaluation of hepatic sinusoidal obstruction syndrome
(HSOS), lung toxicity (CTCAE term pulmonary fibrosis), hepatic toxicity
(according Bearman's criteria) and infections of any CTCAE grade (nonserious
and serious) until day +100.
4. Comparative evaluation of donor-type chimerism on day +28, day
+100 and 12 months after HSCT.
5. Comparative evaluation of overall survival (OS) until 12 months after
HSCT.
6. Comparative evaluation of primary and secondary graft failure until 12
months after HSCT.
7. Comparative evaluation of incidence and severity of acute (until day
+100) and chronic (until 12 months after HSCT) graft versus host
disease (aGvHD/cGvHD).
8. Comparative evaluation of use of rescue therapies including donorlymphocyte
infusions (DLIs), stem cell infusions with or without further
conditioning regimens, re-occurrence of transfusion dependence (i.e.
necessity of regular transfusions of red blood cells or platelets.
9. Evaluation of PK parameters of Treosulfan and its epoxides and to
develop a PK model for assessing relevant covariates.
10. Comparative evaluation of secondary graft failure, cGvHD, donortype
chimerism, OS and TRM during the longer-term follow-up phase.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day +28, day +100 and 12 months after HSCT and/or until the end of the longer-term follow-ip phase.

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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)

Yes

E.8.2.2

Placebo

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

Subsequent to the 12-months follow-up, all patients will be followed on a yearly basis for a minimum of two additional years. This longer-term follow-up phase is scheduled until three years after HSCT of the last
patient enrolled into the study. The end of the trial is defined as last follow-up visit of last subject.

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:

100

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)

F.1.3

Elderly (>=65 years)

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

Children below 18 years of age

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

100

F.4.2.2

In the whole clinical trial

100

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)

After study participation, patients will receive treatment/medical care as routinely used in medical conditions after conditioning treatment and subsequent allogeneic stem cell transplantation.

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

2014-11-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-02-13

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