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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy	Drug: givinostat; Drug: placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 169 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomised, Double Blind, Placebo Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy
• Actual Study Start Date: June 1, 2017
• Estimated Primary Completion Date: March 2022
• Estimated Study Completion Date: March 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. Other functional test as 6MWT [ Time Frame: 18 months ]
   the mean change in 6MWT
2. time to rise from floor [ Time Frame: 18 months ]
   the mean change in time to rise from floor
3. Magnetic Resonance Spetroscopy [ Time Frame: 18 months ]
   the mean change in fat fraction of vastus lateralis muscles at MRS
4. North Star Ambulatory Assessment [ Time Frame: 18 months ]
   the mean change in North Star Ambulatory Assessment
5. 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)

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, California

Neuromuscular Research Center UC Davis Department of Physical Medicine and Rehabilitation

Davis, California, United States, 95817

Rady Children's Hospital center - UCSD Department of Neuroscience

San Diego, California, United States, 92123

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Connecticut

Connecticut Children's Medical Center - Division Neurology

Hartford, Connecticut, United States, 06106

United States, Florida

Child Health Research Institute - Department of Pediatrics

Gainesville, Florida, United States, 32610

Nemours Children's Hospital

Orlando, Florida, United States, 32827

United States, Georgia

MD Rare Disease Research, LLC

Atlanta, Georgia, United States, 30318

United States, Iowa

University of Iowa Children's Hospital

Iowa City, Iowa, United States, 52242

United States, Minnesota

University of Minnesota - Department of Neurology

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Washington University School of Medicine in St Louis - Department of Neurology

Saint Louis, Missouri, United States, 63110

United States, Oregon

Shriners Hospitals for Children

Portland, Oregon, United States, 97239

United States, Pennsylvania

The Children's Hospital of Philadelphia Colket Translational Research Building

Philadelphia, Pennsylvania, United States, 19104

United States, Virginia

Virginia Commonwealth University Childrens Hospital of Richmond at Virginia Commonwealth University

Richmond, Virginia, United States, 23298

Belgium

University Hospitals Leuven, Neuromuscular Reference Centre, Child Neurology

Leuven, Belgium, 03000

Hospital de La Citadelle, Centre de Référence des Maladies Neuromuscolaires (CRMN)

Liege, Belgium, 04000

Canada, Alberta

Kinsmen Research Centre - Alberta Children's Hospital - Alberta Health Services

Calgary, Alberta, Canada, T3B6A8

Canada, British Columbia

The University of British Columbia, Children's and Womens Health Centre of BC Branch

Vancouver, British Columbia, Canada, V6H 3V4

Canada, Ontario

Holland Bloorview Kids Rehabilitation Hospital

Toronto, Ontario, Canada, M4G1R8

France

CHU de Nantes - Hotel-Dieu - Hopital Nord Laennec, rez-de-chausse haut ail Ouest

Nantes, France, 44093

Hopital Armand Trousseau I-Motion, Plateforme d'essais cliniques pédiatriques

Paris, France, 75012

Germany

Universitatsklinikum Essen - Kinder und Jugendmedizin Neuropadiatrie

Essen, Germany, 45122

Klinik un Policlinik fur Kinder und Jugendmedizin - Universitatsklinikum Hamburg Eppendorf

Hamburg, Germany, 20246

Klinikum der Uniersitat Munchen - Campus Innenstadt

Munchen, Germany, 80337

Israel

Institute of Neurology - Schneider Children's Medical Center of Israel Kaplan, 14

Petach-Tikva, Israel, 4920235

Italy

IRCCS Istituto G.Gaslini, U.O.S.D. Centro Traslazionale di Miologia e Patologie Neurodegenerative

Genova, Italy, 16147

A.O.U. Policlinico G. Martino, U.O.C. Neurologia e Malattie Neuromuscolari

Messina, Italy, 98125

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, UOS di Neurologia Pediatrica

Milano, Italy, 20122

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milano, Italy, 20133

Centro Clinico NeMO Fondazione Serena ONLUS Area SUD

Milano, Italy, 20162

Ospedale Pediatrico Bambin Gesù, Malattie Neuromuscolari e Neurodegenerative

Roma, Italy, 00146

Fondazione Policlinico Universitario "A.Gemelli", UOC Neuropsichiatria Infantile

Roma, Italy, 00168

Netherlands

Leiden University Medical Center LUMC

Leiden, Netherlands, ZH 2300 RC

Radboud University Medical Centre

Nijmegen, Netherlands, 6500

Serbia

Clinic of Neurology and Psychiatry for Children and Youth - Neurology Department Dr. Subotic 6a,

Belgrade, Serbia, 11000

Spain

Hospital Sant Joan de Déu - Neuromuscular Pathology Unit

Esplugues de Llobregat, Barcelona, Spain, 08950

Hospital Materno-Infantil - Passeig de la Vall d'Hebron

Barcelona, Spain, 08035

Hospital Universitario Virgen del Rocio

Sevilla, Spain, 41013

Hospital Universitari i Politécnic de la Fe - Servicio Neurologia

Valencia, Spain, 46026

United Kingdom

Alder Hey Children's Hospital NHS Trust

Liverpool, United Kingdom, L12 2AP

UCL Great Ormond Street Institute of Child Health, Dubowitz Neuromuscular Centre and MRC Centre for NMD

London, United Kingdom, EC1N 1EH

The John Walton Muscular Dystrophy Research Centre - Freeman Hospital - Newcastle University - Institute of Genetic Medicine

Newcastle upon Tyne, United Kingdom, NE1 3BZ

The Robert Jones and Agnes Hunt Orthopaedic Hospital - NHS Foundation Trust

Oswestry, United Kingdom, SY 10 7AG

Sponsors and Collaborators

Italfarmaco

Syneos Health

More Information

• Responsible Party: Italfarmaco
• ClinicalTrials.gov Identifier: NCT02851797
• Other Study ID Numbers: EPYDIS (DSC/14/2357/48)
• First Posted: August 2, 2016
• Last Update Posted: September 21, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked