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

NCT ID: NCT02851797

Last Updated: 2023-02-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 179 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-06
• Study Completion Date: 2022-02-22

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.

Detailed Description

This was a phase 3, randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of givinostat in ambulant subjects with DMD. This study included ambulant male paediatric subjects aged ≥ 6 years at baseline affected by DMD.

A total of 179 male ambulant subjects was randomized 2:1 (givinostat: placebo).

Subjects were 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 was planned to be 19 months.

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

Study drug should have been permanently stopped if any of the following occurred:

• 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 have been temporarily stopped if any of the following occurred:

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

In case the study drug was temporarily stopped, the study drug could 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 normalized and/or triglycerides returned to levels below 300 mg/dL (3.42 mmol/L) or diarrhoea was mild.

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

Only one dose reduction was allowed during the treatment period.

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

Conditions

Duchenne Muscular Dystrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

givinostat

Givinostat oral suspension (10 mg/mL) twice daily

Group Type: ACTIVE_COMPARATOR

givinostat

Intervention Type: 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

placebo

Placebo oral suspension (10 mg/mL) twice daily

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

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

Interventions

givinostat

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

Intervention Type: DRUG

placebo

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

Intervention Type: DRUG

Other Intervention Names

ITF2357

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. 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 positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening15.

16. 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);

17. 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;

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).

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Syneos Health

OTHER

Sponsor Role: collaborator

Italfarmaco

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eugenio Mercuri, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS

Locations

Neuromuscular Research Center UC Davis Department of Physical Medicine and Rehabilitation

Davis, California, United States

Rady Children's Hospital center - UCSD Department of Neuroscience

San Diego, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Connecticut Children's Medical Center - Division Neurology

Hartford, Connecticut, United States

Child Health Research Institute - Department of Pediatrics

Gainesville, Florida, United States

Nemours Children's Hospital

Orlando, Florida, United States

MD Rare Disease Research, LLC

Atlanta, Georgia, United States

University of Iowa Children's Hospital

Iowa City, Iowa, United States

University of Minnesota - Department of Neurology

Minneapolis, Minnesota, United States

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

St Louis, Missouri, United States

Shriners Hospitals for Children

Portland, Oregon, United States

The Children's Hospital of Philadelphia Colket Translational Research Building

Philadelphia, Pennsylvania, United States

Virginia Commonwealth University Childrens Hospital of Richmond at Virginia Commonwealth University

Richmond, Virginia, United States

University Hospitals Leuven, Neuromuscular Reference Centre, Child Neurology

Leuven, , Belgium

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

Liège, , Belgium

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

Calgary, Alberta, Canada

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

Vancouver, British Columbia, Canada

Holland Bloorview Kids Rehabilitation Hospital

Toronto, Ontario, Canada

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

Nantes, , France

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

Paris, , France

Universitatsklinikum Essen - Kinder und Jugendmedizin Neuropadiatrie

Essen, , Germany

Klinik un Policlinik fur Kinder und Jugendmedizin - Universitatsklinikum Hamburg Eppendorf

Hamburg, , Germany

Klinikum der Uniersitat Munchen - Campus Innenstadt

München, , Germany

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

Petah Tikva, , Israel

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

Genova, , Italy

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

Messina, , Italy

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

Milan, , Italy

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, , Italy

Centro Clinico NeMO Fondazione Serena ONLUS Area SUD

Milan, , Italy

Ospedale Pediatrico Bambin Gesù, Malattie Neuromuscolari e Neurodegenerative

Roma, , Italy

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

Roma, , Italy

Leiden University Medical Center LUMC

Leiden, , Netherlands

Radboud University Medical Centre

Nijmegen, , Netherlands

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

Belgrade, , Serbia

Hospital Sant Joan de Déu - Neuromuscular Pathology Unit

Esplugues de Llobregat, Barcelona, Spain

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

Barcelona, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

Hospital Universitari i Politécnic de la Fe - Servicio Neurologia

Valencia, , Spain

Alder Hey Children's Hospital NHS Trust

Liverpool, , United Kingdom

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

London, , United Kingdom

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

Newcastle upon Tyne, , United Kingdom

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

Oswestry, , United Kingdom

Countries

United States; Belgium; Canada; France; Germany; Israel; Italy; Netherlands; Serbia; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 38508835 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-000401-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EPYDIS (DSC/14/2357/48)

Identifier Type: -

Identifier Source: org_study_id