Efficacy, Safety and Tolerability of Givinostat in Non-ambulant Patients With Duchenne Muscular Dystrophy
NCT ID: NCT05933057
Last Updated: 2025-05-11
Study Results
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Basic Information
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RECRUITING
PHASE3
138 participants
INTERVENTIONAL
2024-02-19
2028-02-29
Brief Summary
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* 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)
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Detailed Description
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Givinostat, a HDAC inhibitor, was developed for the treatment of DMD based on: (i) the role that increased HDAC activity is thought to exert in contributing to DMD pathogenesis; and (ii) givinostat's ability to counter the pathophysiological and degenerative mechanisms causing muscle insufficiency in boys with DMD.
This study will evaluate the efficacy, safety, and tolerability of givinostat in non-ambulant patients to further corroborate data from the completed phase 3 pivotal study of givinostat in ambulant patients with DMD (ie, Study DSC/14/2357/48, NCT02851797). Primary Objective of the study is to demonstrate the efficacy of givinostat in reducing muscle decline in non-ambulant DMD patients, as measured by Performance of the Upper Limb (PUL) 2.0. Secondary Objectives of the study are to evaluate the safety and tolerability of givinostat in non-ambulant DMD patients, and to further explore the efficacy of givinostat in non-ambulant DMD patients.
A total of 138 patients are planned for enrolment. Patients will be randomised 2:1 to givinostat or placebo and will be treated for 18 months.
The study will be comprised of:
* A screening period, during which eligibility will be confirmed within 4 weeks (±14 days)
* A baseline visit, during which randomisation will be performed
* A double-blind treatment period, during which patients will receive either givinostat or placebo for 18 months (approximately 72 weeks)
* An end of study visit, occurring at Week 72 (±7 days) at the end of the treatment period. At the end of study visit, all the patients (regardless of treatment arm) will be offered enrolment in the long-term safety study DSC/14/2357/51 (NCT03373968) during which they will receive givinostat.
* A follow-up visit, for those patients not consenting to participation in the long-term safety study, that will occur 4 weeks after the end of study visit (ie, Week 76 ±7 days).
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Givinostat
Patients will receive concomitant corticosteroid treatment as part of the standard of care.
Givinostat
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
Patients will receive concomitant corticosteroid treatment as part of the standard of care.
Placebo
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.
Interventions
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Givinostat
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
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
1. 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)
2. Are able to give informed assent and/or consent in writing signed by the patient and/or parent/legal guardian (according to local regulations)
3. A genetic diagnosis of DMD
4. Non-ambulant, defined as being wheelchair bound and:
1. Unable to perform the 10-meter walk/run test (10MWT), or
2. Unable to complete the 10MWT in 30 seconds or less, without any support or devices
5. Performance of the Upper Limb test (PUL version 2.0) entry item scores 3 to 6
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
7. Stable corticosteroids, defined as:
1. Receiving systemic corticosteroids for a minimum of 6 months immediately prior to start of study treatment
2. 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
8. 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:
1. 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
2. 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.
Exclusion Criteria
1. Exposure to another investigational drug within 3 months prior to start of study treatment.
2. Have exposure to any dystrophin restoration product (eg, Ataluren, Exon skipping) within 6 months prior to the start of study treatment
3. Having received any gene therapy (eg, AAV Micro-dystrophin delivery) prior to start of study treatment
4. 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
5. 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
6. Elbow-flexion contractures \>30° in the dominant arm
7. 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
8. Forced Vital Capacity % of predicted \<40%
9. Requirement for daytime ventilator assistance (Note: Night ventilator assistance and use of bi-level positive airway pressure therapy is allowed)
10. Episode of respiratory failure within the 8 weeks prior to screening
11. Symptomatic cardiomyopathy or heart failure and/or left ventricular ejection fraction \<45%
12. 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)
13. Major surgical procedure (including scoliosis surgery) planned within 1 year of the start of study treatment
14. 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
15. Platelets, white blood cells, and/or haemoglobin \< lower limit of normal (LLN) at screening (Note: for abnormal screening laboratory test results \[\<LLN\], the platelets count, white blood cell, and haemoglobin will be repeated once; if the repeat test result is still \<LLN, the patient should be excluded)
16. Fasting triglycerides \>300 mg/dL (3.42 mmol/L) at screening (Note: if the value is \>300 mg/dL, the triglycerides will be repeated once; if the repeated test result is still \>300 mg/dL, the patient should be excluded)
17. Current or history of liver disease or impairment, including but not limited to a baseline elevated total bilirubin (ie, \>1.5 × upper limit of normal \[ULN\]), unless secondary to Gilbert disease or pattern consistent with Gilbert disease
18. Inadequate renal function, as defined by serum Cystatin C result \>2 × ULN (Note: if the value is \>2 × ULN, the serum Cystatin C will be repeated once; if the repeated test result is still \>2 × ULN, the patient should be excluded)
19. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening
20. Hypersensitivity to any component of study medication
21. Sorbitol intolerance or malabsorption, or have the hereditary form of fructose intolerance
22. Diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD, based on Investigator judgement
23. Psychiatric illness or social situations rendering the potential patient unable to understand and comply with the muscle function tests and/or with the study protocol procedures, based on Investigator judgement
24. Have contraindications to MRI scan (eg, claustrophobia, metal implants, or uncontrolled seizure disorder), based on Investigator's judgement.
9 Years
17 Years
MALE
No
Sponsors
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Fortrea
INDUSTRY
Italfarmaco
INDUSTRY
Responsible Party
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Locations
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Universitaire Ziekenhuizen Leuven
Leuven, , Belgium
British Columbia Children's Hospital
Vancouver, British Columbia, Canada
The University of Western Ontario - Children's Health Research Institute
London, Ontario, Canada
University of Ottawa - Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada
University of Toronto - Holland Bloorview Kids Rehabilitation Hospital
Toronto, Ontario, Canada
Centre Hospitalier Régional Universitaire de Lille
Lille, , France
Centre hospitalier universitaire - Hôpitaux de Marseille
Marseille, , France
Hôpital Armand-Trousseau - I-Motion
Paris, , France
Charite-Universitaetsmedizin Berlin
Berlin, , Germany
Universitaetsklinikum Freiburg
Freiburg im Breisgau, , Germany
Associazione La Nostra Famiglia - IRCCS Eugenio Medea - Bosisio Parini
Lecco, , Italy
Fondazione Serena Onlus - Azienda Ospedaliera Niguarda Ca' Granda - NeuroMuscular Omnicentre
Milan, , Italy
Università degli Studi di Padova - Azienda Ospedaliera di Padova
Padua, , Italy
Ospedale Pediatrico Bambino Gesù
Roma, , Italy
Policlinico Universitario Agostino Gemelli - Università Cattolica del Sacro Cuore
Roma, , Italy
Leids Universitair Medisch Centrum (LUMC)
Leiden, , Netherlands
Radboud Universitair Medisch Centrum (Radboudumc)
Nijmegen, , Netherlands
Newcastle upon Tyne Hospitals NHS Foundation Trust - Newcastle University
Newcastle upon Tyne, England, United Kingdom
Oxford University Hospitals NHS Foundation Trust
Oxford, England, United Kingdom
NHS Greater Glasgow and Clyde - Royal Hospital for Children
Glasgow, Scotland, United Kingdom
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
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.
Related Links
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ULYSSES website
Other Identifiers
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2023-503521-19
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
U1111-1295-1799
Identifier Type: OTHER
Identifier Source: secondary_id
1008441
Identifier Type: OTHER
Identifier Source: secondary_id
277453
Identifier Type: OTHER
Identifier Source: secondary_id
DSC/14/2357/50
Identifier Type: -
Identifier Source: org_study_id
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