Efficacy, Safety and Tolerability of Givinostat in Non-ambulant Patients With Duchenne Muscular Dystrophy

NCT05933057 | Recruiting Phase 3 DMC

• 5 other identifiers: DSC/14/2357/502023-503521-19U1111-1295-17991008441277453
• Study Type: interventional
• Target: 138
• Locations: 7 countries
• Sites: 20

Brief Summary

This is a randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy, safety, and tolerability of givinostat in non-ambulant male paediatric (aged 9 to \<18 years) patients with DMD. 138 patients will be randomised 2:1 to givinostat or placebo and will be treated for 18 months.

• Planned screening duration: approximately 4 weeks (±14 days)
• Planned treatment duration: 18 months (approximately 72 weeks)
• Planned follow-up duration: 4 weeks (±7 days) (for patients not participating in the long-term safety study)
• Total duration of study participation: up to 83 weeks (ie, 20-21 months)

Conditions

Duchenne Muscular Dystrophy

Keywords

Duchenne Muscular Dystrophy; givinostat

Outcome Measures

Primary Outcomes (1)

• Change of Performance of Upper Limb 2.0 (PUL) total score at 18 months of treatment of givinostat compared to placebo group.

  The PUL examines 3 major "dimensions" of upper extremity function: shoulder, middle, and distal functions. It includes 22 scored items; a score of 42 (12 for shoulder; 17 for mid-level, and 13 for distal) indicates the highest level of independent function and 0 the lowest.

  Baseline and 18 months

Secondary Outcomes (8)

• Change from baseline of Peak Expiratory Flow percent predicted (PEF%p) at 18 months of treatment of givinostat compared to placebo group

  Baseline and 18 months

• Change from baseline of Forced Vital Capacity percent predicted (FVC%p) at 18 months of treatment of givinostat compared to placebo group

  Baseline and 18 months

• Cumulative loss of PUL total score over 18 months of treatment of givinostat compared to placebo group.

  Baseline to 18 months

• Type, incidence, and severity of treatment-emergent adverse events

  Baseline to 18 months

• Proportion of patients experiencing treatment-emergent adverse events

  Baseline to 18 months

Other Outcomes (14)

• Change from baseline of Fat Fraction of Deltoid and Biceps brachii using Dixon technique at 18 months of treatment of givinostat compared to placebo group

  Baseline and 18 months

• Proportion of responders of givinostat compared to placebo group

  Baseline to 18 months

• Change from baseline of shoulder, elbow and distal level domains of PUL at 18 months of treatment of givinostat compared to placebo group

  Baseline and 18 months

Study Arms (2)

Givinostat

EXPERIMENTAL

Patients will receive concomitant corticosteroid treatment as part of the standard of care.

Drug: Givinostat

Placebo

PLACEBO COMPARATOR

Patients will receive concomitant corticosteroid treatment as part of the standard of care.

Drug: Placebo

Interventions

Givinostat DRUG

Givinostat has to be administered twice daily in a fed state according to a flexible dose regimen based on patient weight. Starting dose could be reduced based on predefined safety rules.

Also known as: ITF2357

Givinostat

Placebo DRUG

Placebo, manufactured to mimic givinostat, has to be administered twice daily in a fed state according to a flexible dose regimen based on patient weight. Starting dose could be reduced based on predefined safety rules.

Placebo

Eligibility Criteria

• Age: 9 Years - 17 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patients must satisfy all the following criteria:
• Children and adolescent males aged ≥ 9 to \<18 years at screening (patients ≥ 18 years of age at screening will not be enrolled into the study)
• Are able to give informed assent and/or consent in writing signed by the patient and/or parent/legal guardian (according to local regulations)
• A genetic diagnosis of DMD
• Non-ambulant, defined as being wheelchair bound and:
• Unable to perform the 10-meter walk/run test (10MWT), or
• Unable to complete the 10MWT in 30 seconds or less, without any support or devices
• Performance of the Upper Limb test (PUL version 2.0) entry item scores 3 to 6
• If on medication for DMD-associated cardiomyopathy (eg, ACE inhibitor, β-blocker, diuretics), stable for ≥1 month immediately prior to start of study treatment, if any
• Stable corticosteroids, defined as:
• Receiving systemic corticosteroids for a minimum of 6 months immediately prior to start of study treatment
• No significant change in dose or dosing regimen (except for adjustments due to body weight change) for a minimum of 6 months immediately prior to start of study treatment
• Willing to use adequate contraception. Effective contraceptive methods must be used from randomisation visit through 3 months after the last dose of study drug, and include the following:
• True abstinence (ie, absence of any sexual intercourse), when in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, post-ovulation, and symptothermal methods) and withdrawal are not acceptable methods of contraception
• Condom with spermicide and the female partner must use an effective method of contraception, such as an oral, transdermal, injectable or implanted hormonal contraceptive; intrauterine device; bilateral tubal occlusion, or a diaphragm or a barrier method of contraception in conjunction with spermicidal jelly such as for example cervical cap with spermicide jelly.

You may not qualify if:

• Patients will be excluded from the study if they satisfy any of the following criteria:
• Exposure to another investigational drug within 3 months prior to start of study treatment.
• Have exposure to any dystrophin restoration product (eg, Ataluren, Exon skipping) within 6 months prior to the start of study treatment
• Having received any gene therapy (eg, AAV Micro-dystrophin delivery) prior to start of study treatment
• Use of any pharmacologic treatment or supplement (other than corticosteroids), that might have had an effect on muscle strength or function within 3 months prior to the start of study treatment (eg, growth hormone); vitamin D, calcium and any other supplements will be allowed
• Use of testosterone, unless used as a replacement therapy for the treatment of delayed puberty. The testosterone dose and regimen should be stable within 6 months prior to the start of study treatment, and circulating testosterone levels should be within the normal ranges for the patient's age
• Elbow-flexion contractures \>30° in the dominant arm
• Inability to perform consistent PUL 2.0 measurement within ±2 points without shoulder domain or within ±3 points with shoulder domain during paired testing at screening
• Forced Vital Capacity % of predicted \<40%
• Requirement for daytime ventilator assistance (Note: Night ventilator assistance and use of bi-level positive airway pressure therapy is allowed)
• Episode of respiratory failure within the 8 weeks prior to screening
• Symptomatic cardiomyopathy or heart failure and/or left ventricular ejection fraction \<45%
• Baseline corrected QT interval using Fredericia's formula (QTcF) \>450 msec (as the mean of 3 consecutive readings 5 minutes apart) or history of additional risk factors for torsades de pointes (eg, heart failure, hypokalaemia, or family history of long QT syndrome)
• Major surgical procedure (including scoliosis surgery) planned within 1 year of the start of study treatment
• Poorly controlled asthma or underlying lung disease such as bronchitis, bronchiectasis, emphysema, recurrent pneumonia that in the opinion of the Investigator might impact respiratory function

Sponsors & Collaborators

• Italfarmaco: lead
• Fortrea: collaborator

Study Sites (20)

Universitaire Ziekenhuizen Leuven

Leuven, 3000, Belgium

RECRUITING

British Columbia Children's Hospital

Vancouver, British Columbia, V6H 3V4, Canada

RECRUITING

The University of Western Ontario - Children's Health Research Institute

London, Ontario, N6A 5W9, Canada

RECRUITING

University of Ottawa - Children's Hospital of Eastern Ontario

Ottawa, Ontario, K1H 8L1, Canada

RECRUITING

University of Toronto - Holland Bloorview Kids Rehabilitation Hospital

Toronto, Ontario, M4G 1R8, Canada

RECRUITING

Centre Hospitalier Régional Universitaire de Lille

Lille, 59037, France

RECRUITING

Centre hospitalier universitaire - Hôpitaux de Marseille

Marseille, 13385, France

RECRUITING

Hôpital Armand-Trousseau - I-Motion

Paris, 75935, France

RECRUITING

Charite-Universitaetsmedizin Berlin

Berlin, 10117, Germany

RECRUITING

Universitaetsklinikum Freiburg

Freiburg im Breisgau, 53113, Germany

RECRUITING

Associazione La Nostra Famiglia - IRCCS Eugenio Medea - Bosisio Parini

Lecco, 23842, Italy

RECRUITING

Fondazione Serena Onlus - Azienda Ospedaliera Niguarda Ca' Granda - NeuroMuscular Omnicentre

Milan, 20162, Italy

RECRUITING

Università degli Studi di Padova - Azienda Ospedaliera di Padova

Padua, 35128, Italy

RECRUITING

Ospedale Pediatrico Bambino Gesù

Roma, 00165, Italy

RECRUITING

Policlinico Universitario Agostino Gemelli - Università Cattolica del Sacro Cuore

Roma, 00165, Italy

RECRUITING

Leids Universitair Medisch Centrum (LUMC)

Leiden, 2300 RC, Netherlands

RECRUITING

Radboud Universitair Medisch Centrum (Radboudumc)

Nijmegen, 6500 HB, Netherlands

RECRUITING

Newcastle upon Tyne Hospitals NHS Foundation Trust - Newcastle University

Newcastle upon Tyne, England, NE1 3BZ, United Kingdom

ACTIVE NOT RECRUITING

Oxford University Hospitals NHS Foundation Trust

Oxford, England, OX3 9DU, United Kingdom

WITHDRAWN

NHS Greater Glasgow and Clyde - Royal Hospital for Children

Glasgow, Scotland, G51 4TF, United Kingdom

ACTIVE NOT RECRUITING

Related Publications (3)

• Bettica P, Petrini S, D'Oria V, D'Amico A, Catteruccia M, Pane M, Sivo S, Magri F, Brajkovic S, Messina S, Vita GL, Gatti B, Moggio M, Puri PL, Rocchetti M, De Nicolao G, Vita G, Comi GP, Bertini E, Mercuri E. Histological effects of givinostat in boys with Duchenne muscular dystrophy. Neuromuscul Disord. 2016 Oct;26(10):643-649. doi: 10.1016/j.nmd.2016.07.002. Epub 2016 Jul 11.

  PMID: 27566866 BACKGROUND

• Consalvi S, Mozzetta C, Bettica P, Germani M, Fiorentini F, Del Bene F, Rocchetti M, Leoni F, Monzani V, Mascagni P, Puri PL, Saccone V. Preclinical studies in the mdx mouse model of duchenne muscular dystrophy with the histone deacetylase inhibitor givinostat. Mol Med. 2013 May 20;19(1):79-87. doi: 10.2119/molmed.2013.00011.

  PMID: 23552722 BACKGROUND

• 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 BACKGROUND

Related Links

• ULYSSES website

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

Central Study Contacts

Italfarmaco Patient Advocacy

CONTACT

+39 02 6443 1; patientadvocacy@italfarmacogroup.com

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: June 16, 2023
• First Posted: July 6, 2023
• Study Start: February 19, 2024
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): February 1, 2028
• Last Updated: May 11, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3); BE (1); FR (3); CA (4); DE (2); IT (5); NL (2)