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Duchenne Muscular DystrophyPhase 3NCT02851797

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

A Phase 3 study testing givinostat in people with Duchenne Muscular Dystrophy, run by Italfarmaco at 42 sites in 11 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 6 to 17 years, men only
Conditions the study is for
Duchenne Muscular Dystrophy
What is being tested?
givinostat
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
179 participants
Where
42 sitesin 11 countries
Study dates
6 Jun 2017to 22 Feb 2022
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 6 to 17 years
  • Men only
  • No healthy volunteers
  • Child

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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;
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  • 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.
  • 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);
  • 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;
  • Have any hypersensitivity to the components of study medication;
  • Have a sorbitol intolerance or sorbitol malabsorption, or have the hereditary form of fructose intolerance.
  • 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.

Trial locations and contacts

42 sites in 11 countries.

42 sites in 11 countries

United States13 sites

  • MD Rare Disease Research, LLC

    Atlanta, Georgia, 30318

  • Children's Hospital Colorado

    Aurora, Colorado, 80045

  • Neuromuscular Research Center UC Davis Department of Physical Medicine and Rehabilitation

    Davis, California, 95817

  • Child Health Research Institute - Department of Pediatrics

    Gainesville, Florida, 32610

  • Connecticut Children's Medical Center - Division Neurology

    Hartford, Connecticut, 06106

  • University of Iowa Children's Hospital

    Iowa City, Iowa, 52242

  • University of Minnesota - Department of Neurology

    Minneapolis, Minnesota, 55455

  • Nemours Children's Hospital

    Orlando, Florida, 32827

  • The Children's Hospital of Philadelphia Colket Translational Research Building

    Philadelphia, Pennsylvania, 19104

  • Shriners Hospitals for Children

    Portland, Oregon, 97239

  • Virginia Commonwealth University Childrens Hospital of Richmond at Virginia Commonwealth University

    Richmond, Virginia, 23298

  • Rady Children's Hospital center - UCSD Department of Neuroscience

    San Diego, California, 92123

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

    St Louis, Missouri, 63110

Other trials in United States

Italy7 sites

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

    Genova, 16147

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

    Messina, 98125

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

    Milan, 20122

  • Fondazione IRCCS Istituto Neurologico Carlo Besta

    Milan, 20133

  • Centro Clinico NeMO Fondazione Serena ONLUS Area SUD

    Milan, 20162

  • Ospedale Pediatrico Bambin Gesù, Malattie Neuromuscolari e Neurodegenerative

    Roma, 00146

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

    Roma, 00168

Other trials in Italy

Spain4 sites

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

    Barcelona, 08035

  • Hospital Sant Joan de Déu - Neuromuscular Pathology Unit

    Esplugues de Llobregat, Barcelona, 08950

  • Hospital Universitario Virgen del Rocio

    Seville, 41013

  • Hospital Universitari i Politécnic de la Fe - Servicio Neurologia

    Valencia, 46026

Other trials in Spain

United Kingdom4 sites

  • Alder Hey Children's Hospital NHS Trust

    Liverpool, L12 2AP

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

    London, EC1N 1EH

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

    Newcastle upon Tyne, NE1 3BZ

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

    Oswestry, SY 10 7AG

Other trials in United Kingdom

Canada3 sites

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

    Calgary, Alberta, T3B6A8

  • Holland Bloorview Kids Rehabilitation Hospital

    Toronto, Ontario, M4G1R8

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

    Vancouver, British Columbia, V6H 3V4

Other trials in Canada

Germany3 sites

  • Universitatsklinikum Essen - Kinder und Jugendmedizin Neuropadiatrie

    Essen, 45122

  • Klinik un Policlinik fur Kinder und Jugendmedizin - Universitatsklinikum Hamburg Eppendorf

    Hamburg, 20246

  • Klinikum der Uniersitat Munchen - Campus Innenstadt

    München, 80337

Other trials in Germany

Belgium2 sites

  • University Hospitals Leuven, Neuromuscular Reference Centre, Child Neurology

    Leuven, 03000

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

    Liège, 04000

Other trials in Belgium

France2 sites

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

    Nantes, 44093

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

    Paris, 75012

Other trials in France

Netherlands2 sites

  • Leiden University Medical Center LUMC

    Leiden, ZH 2300 RC

  • Radboud University Medical Centre

    Nijmegen, 6500

Other trials in Netherlands

Israel1 site

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

    Petah Tikva, 4920235

Other trials in Israel

Serbia1 site

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

    Belgrade, 11000

Other trials in Serbia

About this study

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

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.
Read the 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.

Being tested
givinostat, placebo
Keywords
Dystrophy, DMD, Givinostat
Medical subject headings
Muscular Dystrophy, Duchenne

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • givinostatDrug

    Also called ITF2357

    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

  • placeboDrug

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

Study groups in NCT02851797
Study groupRoleWhat they receive
givinostatActive comparatorGivinostat oral suspension (10 mg/mL) twice daily
Receives: Drug: givinostat
placeboPlacebo comparatorPlacebo oral suspension (10 mg/mL) twice daily
Receives: Drug: placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Baseline and 18 months

Secondary outcomes (8)

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

    An analysis of time (in seconds) to rise from the floor by change from baseline at 18 months is presented for the Target Population in the ITT analysis set. The shorter the time, the better the outcome.

    Measured: Baseline and 18 months

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

    This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes.

    The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment. A modified version of the 6MWT recommended by American Thoracic Society (2002) for use in adults was performed.

    The longer the walked distance the better the outcome.

    Measured: Baseline and 18 months

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

    The total North Star Ambulatory Assessment (NSAA) is a 17-item rating scale that is used to measure functional motor abilities in ambulant children with Duchenne Muscular Dystrophy (DMD). It is usually used to monitor the progression of the disease and treatment effects. The 17 items of the NSAA, ranging from standing to running 10 meters, were graded using the standard score card with each assessment rated as 0 - unable to achieve independently, 1 - modified method but achieves goal independent of physical assistance from another, or 2 - normal with no obvious modification of activity. This scale is ordinal with 0 as the minimum score (indicating full disfunctionality, i.e. the worst outcome) and with 34 as the maximum score indicating fully-independent function (the best outcome).

    Measured: Baseline and 18 months

  4. Cumulative Loss of Function on the NSAA

    Subject cumulative number of failures across all postbaseline visits was the endpoint of interest for analysis.

    For each subject at each postbaseline visit, failure to perform each of the 17 items of the NSAA was assessed, where "failure" was defined as a score transition from 2 or 1 at baseline to 0 at the respective visit. The total number of failed items for the visit was calculated (maximum of 17 failed items per visit per subject). The subject's cumulative number of failures across all visits was the sum of the total failures at each postbaseline visit.

    Measured: over 18 months

  5. Mean Change From Baseline of Muscle Strength Normalized Overtime

    The mean change of muscle strength normalized was evaluated by knee extension and elbow flexion normalized by subject weight, both measured by hand-held myometry (HHM).

    Measured: Baseline and 18 months

  6. Mean Change From Baseline in Vastus Lateralis Muscle Fat Fraction (VL MFF) at 18 Months

    Vastus lateralis muscle fat fraction (VL MFF) was expressed as fat infiltration in this muscle. Fat infiltration was assessed by Magnetic Resonance (MRS).

    Measured: Baseline and 18 months

  7. Number of Subjects Experiencing Treatment-emergent AEs (TEAEs), Serious AEs (SAEs), Mild TEAE Moderate TEAE, Severe TEAE

    Adverse Events are unfavorable changes in health, including abnormal laboratory findings, that occur in trial participants during the clinical trial or within a specified period following the trial.

    Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered Serious Adverse Events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned.

    Measured: Baseline through end of study, that is the end of 18° month

  8. Evaluation of Acceptability/Palatability of the Oral Suspension

    Acceptability and palatability of the oral suspension over time are presented. More in details, child perception of the medicine at the three timepoints hereunder specified; parent perception of the medicine based on the child's reaction at the same three timepoints; and parent problems administering the medication at the same timepoints are reported.

    Measured: Week 4, EOS, early withdrawal

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Aug 2016 (estimated)
  2. Study start6 Jun 2017
  3. Primary completion22 Feb 2022
  4. Study completion22 Feb 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
179 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02851797
Sponsor's protocol ID
EPYDIS (DSC/14/2357/48)
Other IDs
2016-000401-36, 2016
Status last verified
Jan 2023
First submitted
27 Jul 2016
Last updated
2 Feb 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 38508835

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing givinostat in people with Duchenne Muscular Dystrophy, run by Italfarmaco at 42 sites in 11 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 42 sites in United States, Italy, Spain, United Kingdom, Canada and 6 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Feb 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mean Change From Baseline in 4 Standard Stairs (4SC) Climb After 18 Months of Treatment (time frame: Baseline and 18 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02851797, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2023.

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