Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy

• ClinicalTrials.gov Identifier: NCT02851797
• Recruitment Status: Active, not recruiting
• First Posted: August 2, 2016
• Last Update Posted: September 21, 2020
• Sponsor: Italfarmaco
• Collaborator: Syneos Health
• Information provided by (Responsible Party): Italfarmaco

Tracking Information

• First Submitted Date: July 27, 2016
• First Posted Date: August 2, 2016
• Last Update Posted Date: September 21, 2020
• Actual Study Start Date: June 1, 2017
• Estimated Primary Completion Date: March 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 28, 2016)

mean change in 4 standard stairs climb [ Time Frame: 18 months ]

the primary endpoint is the mean change in 4 standard stairs climb test results before and after 18 months of treatment of givinostat versus placebo

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 29, 2019)

• Other functional test as 6MWT [ Time Frame: 18 months ]
  the mean change in 6MWT
• time to rise from floor [ Time Frame: 18 months ]
  the mean change in time to rise from floor
• Magnetic Resonance Spetroscopy [ Time Frame: 18 months ]
  the mean change in fat fraction of vastus lateralis muscles at MRS
• North Star Ambulatory Assessment [ Time Frame: 18 months ]
  the mean change in North Star Ambulatory Assessment
• Muscle strength evaluated by knee extension, elbow flexion [ Time Frame: 18 months ]
  the mean change of muscle strength evaluated by knee extension, elbow flexion as measured by hand-held myometry (HHM)

Original Secondary Outcome Measures (submitted: July 28, 2016)

• Other functional test as 6MWT [ Time Frame: 18 months ]
  the mean change in 6MWT
• time to rise from floor [ Time Frame: 18 months ]
  the mean change in time to rise from floor
• Magnetic Resonance Spetroscopy [ Time Frame: 18 months ]
  the mean change in fat fraction of vastus lateralis muscles at MRS

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy
• Official Title: Randomised, Double Blind, Placebo Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy

Brief Summary

it is a randomised, double blind, parallel group, placebo controlled study. A total of 213 male ambulant subjects will be randomised 2:1 (givinostat:placebo).

Subjects will be stratified for their concomitant use of steroids in 4 strata:

1. Deflazacort daily regimen
2. Deflazacort intermittent regimen
3. Other steroids daily regimen
4. Other steroids intermittent regimen. The study duration is planned for 19 months.

Detailed Description

Givinostat or placebo oral suspension (10 mg/mL) will be administered orally as 2 oral doses daily while the subject is in fed state, according to the child's weight.

Study drug should be permanently stopped if any of the following occur:

• severe drug-related diarrhoea;
• any drug-related Serious Adverse Event;
• QTcF >500 msec;
• platelets count ≤50 x 10^9/L.
• white blood cells ≤2.0 x 10^9/L
• hemoglobin ≤8.0 g/dL

Study drug should be temporarily stopped if any of the following occur:

• moderate or severe diarrhoea.
• platelets count <75 x 10^9/L but >50 x 10^9/L (the treatment should be temporarily stopped and a platelets count has to be performed and re-tested until platelets will be normalized);
• white blood cell <3.0 x 10^9/L but >2.0 x 10^9/L (the treatment should be temporarily stopped and white blood cells have to be measured by 1 week and re-tested until white blood cells will be normalized);
• hemoglobin <10.0 g/dL but > 8.0 g/dL (the treatment should be temporarily stopped and hemoglobin has to be measured by 1 week and re-tested until hemoglobin will be normalized);
• Triglycerides >300 mg/dL (3.42 mmol/L) in fasting condition (the treatment should be temporarily stopped and triglycerides has to be measured every 2 weeks until triglycerides return to levels below 300mg/dL (3.42 mmol/L)

In case the study drug was temporarily stopped, the study drug can be resumed at a level 20% smaller than the one at which the Adverse Event leading to temporary stop occurred, once platelets and/or white blood cell and/or hemoglobin are normalized and/or triglycerides return to levels below 300 mg/dL (3.42 mmol/L) or diarrhoea is mild.

In addition, in case a subject will have a consistent (e.g., at least 2 consecutive evaluations) platelets count ≤150 x 10^9/L and not meeting the stopping criteria for platelets, the Investigator will have to reduce the dose by 20% of the current dose.

Only one dose reduction is allowed during the treatment period.

Two interim analyses are planned and will be conducted by the IDMC in order to ensure study integrity.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Duchenne Muscular Dystrophy

Intervention

• Drug: givinostat
  suspension of givinostat (10 mg/mL)
• Drug: placebo
  suspension manufactured to mimic givinostat

Study Arms

• Active Comparator: givinostat
  Givinostat oral suspension (10 mg/mL) twice daily in a fed state
  Intervention: Drug: givinostat
• Placebo Comparator: placebo
  Placebo oral suspension (10 mg/mL) twice daily in a fed state
  Intervention: Drug: placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: September 18, 2020): 169
• Original Estimated Enrollment (submitted: July 28, 2016): 213
• Estimated Study Completion Date: March 2022
• Estimated Primary Completion Date: March 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Are an ambulant male 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 between ≥3 and <10 seconds at screening
7. Have manual muscle testing (MMT) of quadriceps at screening Grade ≥- 3;
8. Have used systemic corticosteroids for a minimum of 6 months immediately prior to the start of study treatment, with no significant change in corticosteroids type or 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.
9. Subjects must be willing to use adequate contraception.

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 as long as their intake has been stable for 3 months prior to the start of study treatment; Testosterone will also be allowed if it is used as a replacement therapy for the treatment of delayed puberty, and testosterone dose and regimen have been stable for at least 6 months and circulating testosterone levels are within the normal ranges for the subject's age;
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 safety of 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 uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD;
10. Have platelets count at screening < Lower Limit of Normal (LLN);
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;
13. Have inadequate renal function, as defined by serum Cystatin C >2 x the upper limit of normal (ULN);
14. Have Triglycerides > 300 mg/dL (3.42 mmol/L) in fasting condition at screening visit;
15. Have a baseline QTcF >450 msec, 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 known allergic reaction to givinostat or any of its excipients.
18. Have any hypersensitivity to the components of study medication;
19. Have a sorbitol intolerance or sorbitol malabsorption, or have the hereditary form of fructose intolerance.
20. Have contraindications to MRI or MRS (e.g., claustrophobia, metal implants, or seizure disorder).

At the discretion of the Investigator, subjects not meeting inclusion/exclusion criteria may be re-screened twice with an interval of at least 3 months between assessments.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 6 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands, Belgium, Canada, France, Germany, Israel, Italy, Serbia, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02851797
• Other Study ID Numbers: EPYDIS (DSC/14/2357/48)
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Italfarmaco
• Study Sponsor: Italfarmaco
• Collaborators: Syneos Health
• Investigators: Not Provided
• PRS Account: Italfarmaco
• Verification Date: September 2020