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

Randomised, Double Blind, Placebo Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy

it is a randomised, double blind, parallel group, placebo controlled study. A total of 179 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.

Study Overview

• Status: Completed
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Drug: givinostat; Drug: placebo

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.

This trial design a single planned interim analysis. The interim will be governed by an IDMC in order to solely assess futility.

• Study Type: Interventional
• Enrollment (Actual): 179
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 03000
    • University Hospitals Leuven, Neuromuscular Reference Centre, Child Neurology
  • Liege, Belgium, 04000
    • Hospital de La Citadelle, Centre de Référence des Maladies Neuromuscolaires (CRMN)
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B6A8
      • Kinsmen Research Centre - Alberta Children's Hospital - Alberta Health Services
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • The University of British Columbia, Children's and Womens Health Centre of BC Branch
  • Ontario
    • Toronto, Ontario, Canada, M4G1R8
      • Holland Bloorview Kids Rehabilitation Hospital
• France
  • Nantes, France, 44093
    • CHU de Nantes - Hotel-Dieu - Hopital Nord Laennec, rez-de-chausse haut ail Ouest
  • Paris, France, 75012
    • Hopital Armand Trousseau I-Motion, Plateforme d'essais cliniques pédiatriques
• Germany
  • Essen, Germany, 45122
    • Universitatsklinikum Essen - Kinder und Jugendmedizin Neuropadiatrie
  • Hamburg, Germany, 20246
    • Klinik un Policlinik fur Kinder und Jugendmedizin - Universitatsklinikum Hamburg Eppendorf
  • Munchen, Germany, 80337
    • Klinikum der Uniersitat Munchen - Campus Innenstadt
• Israel
  • Petach-Tikva, Israel, 4920235
    • Institute of Neurology - Schneider Children's Medical Center of Israel Kaplan, 14
• Italy
  • Genova, Italy, 16147
    • IRCCS Istituto G.Gaslini, U.O.S.D. Centro Traslazionale di Miologia e Patologie Neurodegenerative
  • Messina, Italy, 98125
    • A.O.U. Policlinico G. Martino, U.O.C. Neurologia e Malattie Neuromuscolari
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Neurologico Carlo Besta
  • Milano, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, UOS di Neurologia Pediatrica
  • Milano, Italy, 20162
    • Centro Clinico NeMO Fondazione Serena ONLUS Area SUD
  • Roma, Italy, 00146
    • Ospedale Pediatrico Bambin Gesù, Malattie Neuromuscolari e Neurodegenerative
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario "A.Gemelli", UOC Neuropsichiatria Infantile
• Netherlands
  • Leiden, Netherlands, ZH 2300 RC
    • Leiden University Medical Center LUMC
  • Nijmegen, Netherlands, 6500
    • Radboud University Medical Centre
• Serbia
  • Belgrade, Serbia, 11000
    • Clinic of Neurology and Psychiatry for Children and Youth - Neurology Department Dr. Subotic 6a,
• Spain
  • Barcelona, Spain, 08035
    • Hospital Materno-Infantil - Passeig de la Vall d'Hebron
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46026
    • Hospital Universitari i Politécnic de la Fe - Servicio Neurologia
  • Barcelona
    • Esplugues de Llobregat, Barcelona, Spain, 08950
      • Hospital Sant Joan de Déu - Neuromuscular Pathology Unit
• United Kingdom
  • Liverpool, United Kingdom, L12 2AP
    • Alder Hey Children's Hospital NHS Trust
  • London, United Kingdom, EC1N 1EH
    • UCL Great Ormond Street Institute of Child Health, Dubowitz Neuromuscular Centre and MRC Centre for NMD
  • Newcastle upon Tyne, United Kingdom, NE1 3BZ
    • The John Walton Muscular Dystrophy Research Centre - Freeman Hospital - Newcastle University - Institute of Genetic Medicine
  • Oswestry, United Kingdom, SY 10 7AG
    • The Robert Jones and Agnes Hunt Orthopaedic Hospital - NHS Foundation Trust
• United States
  • California
    • Davis, California, United States, 95817
      • Neuromuscular Research Center UC Davis Department of Physical Medicine and Rehabilitation
    • San Diego, California, United States, 92123
      • Rady Children's Hospital center - UCSD Department of Neuroscience
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center - Division Neurology
  • Florida
    • Gainesville, Florida, United States, 32610
      • Child Health Research Institute - Department of Pediatrics
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • MD Rare Disease Research, LLC
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota - Department of Neurology
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine in St Louis - Department of Neurology
  • Oregon
    • Portland, Oregon, United States, 97239
      • Shriners Hospitals for Children
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia Colket Translational Research Building
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Childrens Hospital of Richmond at Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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. Loss of ≥30 degrees of plantar flexion from the normal range of movement at the ankle joint due to contracture (i.e. fixed loss of more than 10 degrees of plantar flexion from plantigrade, assuming normal range of dorsiflexion of 20 degrees;
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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: givinostat; Givinostat oral suspension (10 mg/mL) twice daily in a fed state	Drug: givinostat; suspension of givinostat (10 mg/mL)
Placebo Comparator: placebo; Placebo oral suspension (10 mg/mL) twice daily in a fed state	Drug: placebo; suspension manufactured to mimic givinostat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mean change in 4 standard stairs climb	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	18 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Italfarmaco
• Collaborators: Syneos Health

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): February 22, 2022
• Study Completion (Actual): February 22, 2022

Study Registration Dates

• First Submitted: July 27, 2016
• First Submitted That Met QC Criteria: July 28, 2016
• First Posted (Estimate): August 2, 2016

Study Record Updates

• Last Update Posted (Actual): June 10, 2022
• Last Update Submitted That Met QC Criteria: June 9, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: EPYDIS (DSC/14/2357/48)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No