Clinical Trials Register

Summary
EudraCT Number:	2017-001629-41
Sponsor's Protocol Code Number:	DSC/15/2357/53
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-05-31
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

Netherlands - Competent Authority

A.2

EudraCT number

2017-001629-41

A.3

Full title of the trial

A randomised, double-blind, placebo-controlled study to evaluate the micro-macroscopic effects on muscles, the safety and tolerability, and the efficacy of
givinostat in patients with Becker Muscular Dystrophy

A.3.1

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

Study to evaluate the micro-macroscopic effects on muscles, the safety and tolerability, and the efficacy of givinostat in patients with Becker Muscular Dystrophy

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

DSC/15/2357/53

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	ITALFARMACO S.P.A.
B.1.3.4	Country	Italy
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	ITALFARMACO S.P.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ITALFARMACO S.P.A.
B.5.2	Functional name of contact point	Clinical Research and Development
B.5.3	Address:
B.5.3.1	Street Address	Via dei Lavoratori 54
B.5.3.2	Town/ city	Cinisello Balsamo
B.5.3.3	Post code	20092
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390264431
B.5.5	Fax number	00390264433554
B.5.6	E-mail	p.bettica@italfarmaco.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	No
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/3/12/1009
D.3 Description of the IMP
D.3.1	Product name	Givinostat (hydrochloride monohydrate)
D.3.2	Product code	ITF2357
D.3.4	Pharmaceutical form	Oral suspension
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	Givinostat (hydrochloride monohydrate)
D.3.9.1	CAS number	732302-99-7
D.3.9.2	Current sponsor code	ITF2357
D.3.9.3	Other descriptive name	GIVINOSTAT
D.3.9.4	EV Substance Code	SUB30834
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	10
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	Oral suspension
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

Distrofia Muscolare di Becker (DMB)

E.1.1.1

Medical condition in easily understood language

Genetic disease characterized by degeneration of muscle fibers

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

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	10059117
E.1.2	Term	Becker's muscular dystrophy
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic 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 establish the histological effects of givinostat versus placebo administered over 12 months.

E.2.2

Secondary objectives of the trial

To establish the macroscopic muscle effects of givinostat versus placebo administered chronically over 12 months assessed by MRI/MRS.
• To establish the other histological effects of givinostat versus placebo administered over 12 months.
• To establish the efficacy of givinostat versus placebo administered chronically over 12 months in slowing disease progression.
• To assess the safety and tolerability of givinostat versus placebo administered chronically.
• To evaluate the pharmacokinetic (PK) profile of givinostat administered chronically in the target population.
• To evaluate the impact of givinostat versus placebo administered chronically on quality of life and activities of daily living.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Ambulant male patients aged ≥18 years to < 65 years at randomization with BMD diagnosis confirmed by genetic testing.
2. Able and willing to give informed consent in writing.
3. Able to perform 6MWT at screening with a minimum distance of 200 m and maximum distance of 450 m.
4. If in treatment with systemic corticosteroids and/or ACE inhibitor, and/or β or α adrenergic receptor blocker, no significant
change in dosage or dosing regimen (excluding changes related to body weight change) for a minimum of 6 months immediately
prior to start of study treatment.
5. Patients must be willing to use adequate contraception. Contraceptive methods must be used from Randomization through 3
months after the last dose of study treatment.

E.4

Principal exclusion criteria

1. Exposure to another investigational drug within 3 months prior to the start of study treatment.
2. Use of any pharmacologic treatment, other than corticosteroids, that might have an effect on muscle strength or function within
3 months prior to the start of study treatment (e.g., growth hormone). Vitamin D, calcium, and any other supplements will be
allowed.
3. Surgery that might affect muscle strength or function within 3 months before study entry or planned surgery at any time during
the study.
4. Presence of other clinically significant disease that in the Investigator’s opinion could adversely affect the safety of the patient,
making it unlikely that the course of treatment or follow-up is completed, or could impair the assessment of study results.
5. A diagnosis of other uncontrolled neurological diseases or presence of relevant somatic disorders not related to BMD that may interfere with the ability to perform the muscle function tests and/or to comply with the study protocol procedures.
6. Platelet count, WBC count and hemoglobin at screening < Lower Limit of Normal (LLN). If laboratory screening results are < LLN,
platelet count, WBC count and hemoglobin are to be repeated once, and if again < LLN become exclusionary.
7. Symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction <
50% at screening or with heart transplant.
8. Current liver disease or impairment, including but not limited to elevated total bilirubin (> 1.5 x ULN), unless secondary to
Gilbert’s disease or pattern consistent with Gilbert's disease.
9. Inadequate renal function, as defined by serum Cystatin C > 2 x the upper limit of normal (ULN). If the value is > 2 x ULN,
serum Cystatin C will be repeated once, and if again > 2 x ULN becomes exclusionary.
10. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening.
11. Baseline corrected QT interval, Fredericia’s correction (QTcF) > 450 msec, (as the mean of 3 consecutive readings 5 minutes
apart) or history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, or family history of long QT
syndrome).
12. Current psychiatric illness/social situations rendering the potential patient unable to understand and comply with the muscle function
tests and/or with the study protocol procedures.
13. Hypersensitivity to the components of study medication.
14. Sorbitol intolerance or sorbitol malabsorption, or the hereditary form of fructose intolerance.
15. Contraindications to muscle biopsy.
16. Contraindications to MRI/MRS (e.g., claustrophobia, metal implants, or seizure disorder).
17. Hypertriglyceridemia (> 1.5 x upper limit of normal [ULN])*
* At screening, patients with hypertriglyceridemia can be enrolled if in stable treatment and with controlled levels of triglycerides (i.e. within normal range) for at least six months.

E.5 End points

E.5.1

Primary end point(s)

Mean change in mean Cross Sectional Area (CSA) comparing the histology of muscle biopsies

E.5.1.1

Timepoint(s) of evaluation of this end point

Before and after 12 months of treatment with givinostat versus placebo

E.5.2

Secondary end point(s)

1. Mean change in fat fraction of vastus lateralis and soleus comparing Magnetic Resonance Spectroscopy (MRS);
2. Mean change in fat fraction of pelvic girdle and lower limb muscles comparing Magnetic Resonance Imaging (MRI);
3 .Mean CSA of pelvic girdle and lower limb muscles comparing MRI;
4. Mean change in other histology parameters (e.g. MFA%, % of total fibrosis, regenerative fibers) comparing the histology biopsies;
5. Mean change in Motor Function Measurement (MFM);
6. Mean change in Time Function Tests (time to climb four standard steps, time to rise from floor and time to walk/run 10 m);
7. Mean change in 6 Minute Walking Test (6MWT);
8. Proportion of patients with < 10% worsening in 6MWT;
9. Proportion of patients who lose the ability to rise from floor;
10. Proportion of patients who lose ambulation;
11. Mean change in muscle strength evaluated by knee extension, elbow flexion as measured by Hand Held Myometry (HHM);
12. Mean changes in quality of life (assessed by the 36-item Short Form survey [SF36]);

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Before and after 12 months of treatment with givinostat versus placebo;
2. Before and after 12 months of treatment with givinostat versus placebo;
3. Before and after 12 months of treatment with givinostat versus placebo;
4. Before and after 12 months of treatment with givinostat;
5. Before and after 12 months of treatment with givinostat versus placebo;
6. Before and after 12 months of treatment with givinostat versus placebo;
7. Before and after 12 months of treatment with givinostat versus placebo;
8. At the end of study;
9. Baseline through end of study;
10. During the study;
11. Before and after 12 months of treatment with givinostat versus placebo;
12. Before and after 12 months of treatment with givinostat as compared to placebo;

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

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

Yes

E.6.13.1

Other scope of the trial description

Quality of life and daily activities

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

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

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:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

At the end of the study, the patient will return to his usual medical care.

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	Parent Project Onlus
G.4.3.4	Network Country	Italy
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Association Aide aux Familles d’Enfants Handicapés Moteur (AFEHM)
G.4.3.4	Network Country	France

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-05-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-03-19

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