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

NCT02851797 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: EPYDIS (DSC/14/2357/48)2016-000401-36
• Study Type: interventional
• Target: 179
• Locations: 11 countries
• Sites: 42

Brief Summary

Primary Objective The primary objective of the study was to establish the effects of givinostat versus placebo administered chronically over 18 months to slow disease progression in ambulant DMD subjects. Secondary Objectives The secondary objectives of this study were:

• To assess the safety and tolerability of givinostat versus placebo administered chronically in DMD subjects
• To evaluate the PK profile of givinostat administered chronically in DMD subjects
• To evaluate the impact on quality of life (QoL) and activities of daily living of givinostat versus placebo administered chronically.

Conditions

Duchenne Muscular Dystrophy

Keywords

Dystrophy; DMD; Givinostat

Outcome Measures

Primary Outcomes (1)

• Mean Change From Baseline in 4 Standard Stairs (4SC) Climb After 18 Months of Treatment

  The time (in seconds) to climb 4 standard-sized stairs is a TFT that represents stair-climbing ability. The test was evaluated by qualified functional evaluators (ie, physiotherapists) who were different from the site personnel who reviewed subjects' safety results. The test was performed in a standardised manner described in a specific site manual. Baseline 4SC was the measurement taken at the randomization assessment, unless this was missing, in which case baseline was taken as the last non missing value recorded prior to or on the date of first study treatment. The shorter the time, the better the outcome.

  Baseline and 18 months

Secondary Outcomes (8)

• Mean Change From Baseline in Time to Rise From Floor After 18 Months of Treatment

  Baseline and 18 months

• Mean Change From Baseline in the Six-minute Walking Test (6MWT) After 18 Months of Treatment

  Baseline and 18 months

• Mean Change From Baseline in Total North Star Ambulatory Assessment (NSAA) Score After 18 Months of Treatment

  Baseline and 18 months

• Cumulative Loss of Function on the NSAA

  over 18 months

• Mean Change From Baseline of Muscle Strength Normalized Overtime

  Baseline and 18 months

Study Arms (2)

givinostat

ACTIVE COMPARATOR

Givinostat oral suspension (10 mg/mL) twice daily

Drug: givinostat

placebo

PLACEBO COMPARATOR

Placebo oral suspension (10 mg/mL) twice daily

Drug: placebo

Interventions

givinostat DRUG

The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose * \> or =10 and \< 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid * \> or =12.5 and \< 20 kg: 16.7 mg bid =1.7 ml oral suspension bid * \> or = 20 and \< 25 kg: 20 mg bid = 2.0 ml oral suspension bid * \> or = 25 and \< 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid * \> or = 30 and \< 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid * \> or = 40 and \< 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid * \> or = 50 and \< 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid * \> or = 60 and \< 70 kg: 40 mg bid = 4 ml oral suspension bid * \> or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid

Also known as: ITF2357

givinostat

placebo DRUG

The oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.

placebo

Eligibility Criteria

• Age: 6 Years - 17 Years
• Gender Eligibility Details: to take part in the study, subjects should be: 1\) ambulant males aged ≥ 6 years at randomization with DMD-characteristic clinical symptoms or signs (eg, proximal muscle weakness, Gowers' maneuver, elevated serum creatinine kinase level) already present at screening, 2. should have a DMD diagnosis confirmed by genetic testing
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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;
• Have DMD diagnosis confirmed by genetic testing;
• Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to local regulations);
• 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;
• Have the mean of 2 screening 4SC assessments ≤8 seconds;
• Have time to rise from floor between ≥3 and \<10 seconds at screening
• Have manual muscle testing (MMT) of quadriceps at screening Grade ≥- 3;
• 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.
• Subjects must be willing to use adequate contraception.

You may not qualify if:

• Have exposure to another investigational drug within 3 months prior to the start of study treatment;
• Have exposure to idebenone within 3 months prior to the start of study treatment;
• Have exposure to any dystrophin restoration product (e.g., Ataluren, Exon skipping) within 6 months prior to the start of study treatment;
• 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;
• 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;
• 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;
• 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;
• 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;
• Have a diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD;
• Have platelets count at screening \< Lower Limit of Normal (LLN);
• Have symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction \<50% at screening;
• Have a current or history of liver disease or impairment;
• Have inadequate renal function, as defined by serum Cystatin C \>2 x the upper limit of normal (ULN);
• Have Triglycerides \> 300 mg/dL (3.42 mmol/L) in fasting condition at screening visit;
• Have a positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening15.

Sponsors & Collaborators

• Italfarmaco: lead
• Syneos Health: collaborator

Study Sites (42)

Neuromuscular Research Center UC Davis Department of Physical Medicine and Rehabilitation

Davis, California, 95817, United States

Location

Rady Children's Hospital center - UCSD Department of Neuroscience

San Diego, California, 92123, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Connecticut Children's Medical Center - Division Neurology

Hartford, Connecticut, 06106, United States

Location

Child Health Research Institute - Department of Pediatrics

Gainesville, Florida, 32610, United States

Location

Nemours Children's Hospital

Orlando, Florida, 32827, United States

Location

MD Rare Disease Research, LLC

Atlanta, Georgia, 30318, United States

Location

University of Iowa Children's Hospital

Iowa City, Iowa, 52242, United States

Location

University of Minnesota - Department of Neurology

Minneapolis, Minnesota, 55455, United States

Location

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

St Louis, Missouri, 63110, United States

Location

Shriners Hospitals for Children

Portland, Oregon, 97239, United States

Location

The Children's Hospital of Philadelphia Colket Translational Research Building

Philadelphia, Pennsylvania, 19104, United States

Location

Virginia Commonwealth University Childrens Hospital of Richmond at Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

University Hospitals Leuven, Neuromuscular Reference Centre, Child Neurology

Leuven, 03000, Belgium

Location

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

Liège, 04000, Belgium

Location

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

Calgary, Alberta, T3B6A8, Canada

Location

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

Vancouver, British Columbia, V6H 3V4, Canada

Location

Holland Bloorview Kids Rehabilitation Hospital

Toronto, Ontario, M4G1R8, Canada

Location

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

Nantes, 44093, France

Location

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

Paris, 75012, France

Location

Universitatsklinikum Essen - Kinder und Jugendmedizin Neuropadiatrie

Essen, 45122, Germany

Location

Klinik un Policlinik fur Kinder und Jugendmedizin - Universitatsklinikum Hamburg Eppendorf

Hamburg, 20246, Germany

Location

Klinikum der Uniersitat Munchen - Campus Innenstadt

München, 80337, Germany

Location

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

Petah Tikva, 4920235, Israel

Location

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

Genova, 16147, Italy

Location

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

Messina, 98125, Italy

Location

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

Milan, 20122, Italy

Location

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, 20133, Italy

Location

Centro Clinico NeMO Fondazione Serena ONLUS Area SUD

Milan, 20162, Italy

Location

Ospedale Pediatrico Bambin Gesù, Malattie Neuromuscolari e Neurodegenerative

Roma, 00146, Italy

Location

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

Roma, 00168, Italy

Location

Leiden University Medical Center LUMC

Leiden, ZH 2300 RC, Netherlands

Location

Radboud University Medical Centre

Nijmegen, 6500, Netherlands

Location

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

Belgrade, 11000, Serbia

Location

Hospital Sant Joan de Déu - Neuromuscular Pathology Unit

Esplugues de Llobregat, Barcelona, 08950, Spain

Location

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

Barcelona, 08035, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, 41013, Spain

Location

Hospital Universitari i Politécnic de la Fe - Servicio Neurologia

Valencia, 46026, Spain

Location

Alder Hey Children's Hospital NHS Trust

Liverpool, L12 2AP, United Kingdom

Location

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

London, EC1N 1EH, United Kingdom

Location

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

Newcastle upon Tyne, NE1 3BZ, United Kingdom

Location

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

Oswestry, SY 10 7AG, United Kingdom

Location

Related Publications (1)

• Mercuri E, Vilchez JJ, Boespflug-Tanguy O, Zaidman CM, Mah JK, Goemans N, Muller-Felber W, Niks EH, Schara-Schmidt U, Bertini E, Comi GP, Mathews KD, Servais L, Vandenborne K, Johannsen J, Messina S, Spinty S, McAdam L, Selby K, Byrne B, Laverty CG, Carroll K, Zardi G, Cazzaniga S, Coceani N, Bettica P, McDonald CM; EPIDYS Study Group. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X.

  PMID: 38508835 DERIVED

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

givinostat; givinostat hydrochloride

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Dr Paolo Bettica, MD and PhD
• Organization: Italfarmaco SpA

p.bettica@italfarmacogroup.com

+3902 66041503

Study Officials

• Eugenio Mercuri, MD, PhD

  Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2016
• First Posted: August 2, 2016
• Study Start: June 6, 2017
• Primary Completion: February 22, 2022
• Study Completion: February 22, 2022
• Last Updated: February 2, 2023
• Results First Posted: February 2, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (3); IT (7); SE (1); IL (1); NL (2); ES (4); CA (3); FR (2); GB (4); BE (2); US (13)