Study to evaluate the efficacy and safety of givinostat in ambulant patients with Duchenne Muscular Dystrophy.

• Register: EUCTR
• Last refreshed on: 20 February 2017
• Main ID: EUCTR2016-000401-36-ES
• Date of registration: 10/02/2017
• Prospective Registration: Yes
• Primary sponsor: ITALFARMACO S.p.A.
• Public title: Study to evaluate the efficacy and safety of givinostat in ambulant patients with Duchenne Muscular Dystrophy.
• Scientific title: Randomised, double blind, placebo controlled, multicentre study to evaluate the efficacy and safety of givinostat in ambulant patients with Duchenne Muscular Dystrophy.
• Date of first enrolment: 10/02/2017
• Target sample size: 192
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000401-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Spain, United Kingdom, United States

Contacts

• Name: Clinical Research and Development
• Affiliation: ITALFARMACO S.p.A.

• Name: Clinical Research and Development
• Affiliation: ITALFARMACO S.p.A.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Are ambulant males aged =6 years at randomisation with DMD characteristic clinical symptoms or signs (e.g., proximal muscle weakness, Gowers’ maneuver, elevated serum creatinine kinase level) already present at screening;
2. Have DMD diagnosis confirmed by genetic testing;
3. Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to local regulations);
4. Are able to complete 2 Four Stairs Climb test (4SC) screening assessments; the results of these tests must be within ±1 second of each other;
5. Have the mean of 2 screening 4SC assessments =8 seconds;
6. Have time to rise from floor of <10 seconds at screening;
7. Have manual muscle testing (MMT) of quadriceps at screening = Grade 3;
8. Are eligible according to the protocol-specified functional algorithm predictive of vastus lateralis muscle fat fraction (VL MFF) that should be in the range >10% but <30%;
9. Have used systemic corticosteroids for a minimum of 6 months immediately prior to the start of study treatment, with 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 and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study.
10. Subjects must be willing to use adequate contraception.
Contraceptive methods must be used from Randomization Visit 3 through 3 months after the last dose of study drug, and include the following:
• True abstinence (absence of any sexual intercourse), when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
• Condom with spermicide and the female partner must use an acceptable method of contraception, such as an oral, transdermal, injectable or implanted steroid-based contraceptive, or a diaphragm or a barrier method of contraception in conjunction with spermicidal jelly such as for example cervical cap with spermicide jelly.
Are the trial subjects under 18? yes
Number of subjects for this age range: 192
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range 0
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
1. Have exposure to another investigational drug within 3 months prior to the start of study treatment;
2. Have exposure to idebenone within 3 months prior to the start of study treatment;
3. Have exposure to any dystrophin restoration product (e.g., Ataluren, Exon-skipping) within 6 months prior to the start of study treatment;
4. Use of any pharmacologic treatment, other than corticosteroids, that might have had 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;
5. Have surgery that might have an effect on muscle strength or function within 3 months before study entry or planned surgery at any time during the study;
6. Ankle joint contractures due to a fixed loss of =10 degrees of dorsiflexion from plantagrade assuming a normal range of dorsiflexion of 20 degree;
7. Change in contracture treatment such as serial casting, contracture control devices, night splints, stretching exercises (passive, active, self) within 3 months prior to enrollment, or expected need for such intervention during the study;
8. Have presence of other clinically significant disease, which, in the Investigator’s opinion, could adversely affect the safetyof the subject, making it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results;
9. Have a diagnosis of other neurological diseases or presence of relevant somatic disorders that are not related to DMD;
10. Have platelets count, White Blood Cell and Hemoglobin at screening 11. Have symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction <50% at screening;
12. Have a current or history of liver disease or impairment; including but not limited to an elevated total bilirubin (i.e. > 1.5 x ULN), unless secondary to Gilbert disease or pattern consistent with Gilbert's;
13. Have inadequate renal function, as defined by serum Cystatin C >2 x the upper limit of normal (ULN). If the value is >2 x ULN, the serum Cystatin C will be repeated once; if the repeated test result is still >2 x ULN, the subject should be excluded);
14. Have a positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening;
15. Have a baseline corrected QT interval, Fridericia’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);
16. Have a psychiatric illness/social situations rendering the potential subject unable to understand and comply with the muscle function tests and/or with the study protocol procedures;
17. Have any hypersensitivity to the components of study medication;
18. Have a sorbitol intolerance or sorbitol malabsorption, or have the hereditary form of fructose intolerance.

For the subgroup of subjects who will perform the magnetic resonance imaging (MRI) and spetroscopy (MRS) (i.e., MR Cohort):
19.Have contraindications to MRI or MRS (e.g., claustrophobia,
metal implants, or seizure disorder).


Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Duchenne Muscular Dystrophy (DMD)
MedDRA version: 19.1 Level: PT Classification code 10013801 Term: Duchenne muscular dystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Name: Givinostat (hydrochloride monohydrate)
Product Code: ITF2357
Pharmaceutical Form: Oral suspension
INN or Proposed INN: Givinostat (hydrochloride monohydrate)
CAS Number: 732302-99-7
Current Sponsor code: ITF2357
Other descriptive name: GIVINOSTAT
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Oral suspension
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To establish the effects of givinostat versus placebo administered chronically over 18 months to slow disease progression in ambulant DMD subjects

Primary end point(s): Mean change in 4SC before and after 18 months of treatment of givinostat versus placebo.

Secondary Objective: To assess the safety and tolerability of givinostat versus placebo administered chronically in DMD subjects.
To evaluate the pharmacokinetic (PK) profile of givinostat administered chronically in the target population.
To evaluate the impact on quality of life and activities of daily living of givinostat versus placebo administered chronically.

Exploratory objectives:
To evaluate the correlation between PK profile of givinostat and pharmacodynamics (PD) data.
To explore whether the effects of givinostat versus placebo administered chronically may be related to the type of DMD mutation or to the biomarkers.

Timepoint(s) of evaluation of this end point: 18 months

Secondary Outcome(s)

Secondary end point(s): Key endpoints (all subjects):
Mean change in time to rise from floor before and after 18 months of treatment of givinostat versus placebo;
Mean change in 6MWT before and after 18 months of treatment of givinostat versus placebo;
Mean change in muscle strength evaluated by knee extension, elbow flexion as measured by HHM, before and after 18 months of treatment of givinostat versus placebo.

Key endpoints (MR cohort):
• Mean change in fat fraction of vastus lateralis muscles comparing the MRS before and after 12 months of treatment of givinostat versus placebo;
• Mean change in 4SC before and after 12 months of treatment of givinostat versus placebo;
• Mean change in time to rise from floor before and after 12 months of treatment of givinostat versus placebo;
• Mean change in 6MWT before and after 12 months of treatment of givinostat versus placebo;
• Mean change in muscle strength evaluated by knee extension before and after 12 months of treatment of givinostat versus placebo;
• Mean change in fat fraction of vastus lateralis muscles comparing the MRS before and after 18 months of treatment of givinostat versus placebo

Safety endpoints:
- Number of subjects experiencing treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) (Baseline through end of study [EOS]);
- Type, incidence, and severity of TEAEs and SAEs (Baseline through EOS);
- Changes from baseline to end of study of:
o Vital signs and clinical laboratory tests (blood chemistry and hematology);
o Respiratory function evaluated by forced vital capacity (FVC), forced expiratory volume at 1 second (FEV1), FVC/FEV1, Peak Expiratory Flow (PEF);
o Cardiac function evaluated by ECG and ECHO;
o Cognitive function evaluated by the Raven progressive matrices;
o Weight, height, and body mass index (BMI).
o Evaluation of acceptability/palatability of the oral suspension.

Pharmacokinetic Endpoints:
- Description of the PK of givinostat and its major metabolites:
ITF2374 and ITF2375 in the subject population;
- Identification of the relevant demographic and pathophysiological covariates influencing the PK of givinostat.

Exploratory endpoints:
• Mean changes before and after 12 months of treatment of givinostat versus placebo of:
o time to 4SC;
o time to rise from floor;
o 6MWT;
o muscle strength.
• Mean changes before and after 12 and 18 months of treatment of givinostat as compared to placebo of:
o time to walk/run 10 meters;
o physical function as measured by NSAA;
o PODCI scores.
• Mean changes before and after 18 months of treatment of givinostat as compared to placebo of:
o %-predicted 6MWT;
o Only in the MR cohort: MRI parameters (e.g., fat fraction of thigh muscles, CSA of vastus lateralis and other thigh muscles).
• Time to 10% persistent worsening in 6MWT (Baseline through end of study);
• Proportion of subjects with =10% worsening in 6MWT at end of study;
• Time to loss of standing (Baseline through end of study);
• Proportion of subjects who loose ambulation during the study;
• PK-PD analyses: relationships between metrics of exposure and efficacy/safety endpoints of givinostat.

Timepoint(s) of evaluation of this end point: timepoint given in endpoint

Secondary ID(s)

DSC/14/2357/48

126598

Source(s) of Monetary Support

ITALFARMACO S.p.A.