Givinostat in Duchenne's Muscular Dystrophy Long-term Safety and Tolerability Study

Open Label, Long-term Safety, Tolerability, and Efficacy Study of GIVINOSTAT in All DMD Patients Who Have Been Previously Treated in One of the GIVINOSTAT Studies

This is an open label, long-term safety, tolerability, and efficacy study of GIVINOSTAT in all DMD (Duchenne's muscular dystrophy) patients who have been previously treated in one of the GIVINOSTAT studies.

Study Overview

• Status: Enrolling by invitation
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Drug: Givinostat

Detailed Description

GIVINOSTAT oral suspension (10 mg/mL) has to be administered orally as 2 oral doses daily while the subject is in a fed state. The starting dose of GIVINOSTAT in the present long term study will be the same that the subject was receiving at the end of the previous DMD GIVINOSTAT study.

As weight affects GIVINOSTAT exposures, the dosage will be modified based on subject weight according the rules detailed in the study protocol section 11.2.2.1.

In addition, in case a subject will have a consistent (e.g., at least 2 consecutive evaluations) platelets count ≤150 x 10^9/L and not meet the stopping criteria for platelets, the Investigator will have to reduce the dose of 1/3 or 20% less of the current dose as described in the study protocol section 10.5.1.3. During the first month of treatment, platelets count assessment will be performed weekly, while during the second month it will be performed every 2 weeks, in order to strictly monitor this parameter for safety reasons, with the exclusion of subjects coming from study DSC/11/2357/43 for which the first visit will be 4 months after the Visit 1/baseline visit.

Study drug should be permanently interrupted if any of the following occurs:

• severe drug-related diarrhoea (i.e., increase of ≥7 stools per day);
• any drug-related SAE;
• QTcF >500 msec;
• platelets count ≤50 x 10^9/L;
• white blood cells ≤2.0 x 10^9/L;
• hemoglobin ≤8.0 g/dL; To avoid laboratory errors and anomalous values, test must be confirmed with a repeated test performed on the next working day. The treatment should be stopped until the retest result becomes available. If the repeated test is still under the stopping limit value, study drug must be permanently discontinued. If the repeated test is acceptable, the subject can resume treatment.

The Investigator will follow up the patient until resolution or acceptable stabilization of the event occurs and document all the relevant information, as applicable. After the resolution/stabilization of the event, the subject will be withdrawn from the study and the EOS Visit (see Section 12.1.10) will be performed.

Any decision relevant to the dose adjustment and/or modification of schedule of assessments can be discussed with the Medical Monitor, but the final decision remains with the Investigator only or its authorized designee.

• Study Type: Interventional
• Enrollment (Estimated): 206
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 03000
    • University Hospitals Leuven, Neuromuscular Reference Centre, Child Neurology
  • Liège, Belgium, 04000
    • Hospital de La Citadelle, Centre de Référence des Maladies Neuromuscolaires (CRMN)
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Kinsmen Research Centre - Alberta Children's Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • The University of British Columbia, Children's and Womens Health Centre of BC Branch
  • Ontario
    • Toronto, Ontario, Canada, M4G1R8
      • Holland Bloorview Kids Rehabilitation Hospital
• France
  • Nantes, France, 44093
    • CHU de Nantes - Hotel-Dieu - Hopital Nord Laennec, rez-de-chausse haut ail Ouest
  • Paris, France, 760
    • Hôpital Armand Trousseau I-Motion - Plateforme d'essais cliniques pédiatriques Bâtiment Lemariey - Porte 20 * 2ème étage 26 Avenue du Dr Arnold Nette
• Germany
  • Essen, Germany, D-45147
    • Universitätsklinikum Essen - Kinder-und Jugendmedizin Neuropadiatrie
  • Hamburg, Germany, 20246
    • Klinik- und Poliklinik fur Kinder- und Jugendmedizin, Universitatsklinikum HamburgEppendorf, Martinistr. 52
  • München, Germany, 80337
    • Klinikum der Universitat Munchen, Campus Innenstadt, Lindwurmstr. 4
• Israel
  • Petach-Tikva, Israel, 4920235
    • Institute of Neurology - Schneider Children's Medical Center of Israel Kaplan, 14
• Italy
  • Genova, Italy, 16147
    • U.O.S.D. Centro Traslazionale di Miologia e Patologie Neurodegenerative, Building 16 - ground floor IRCCS Istituto Giannina Gaslini,
  • Messina, Italy, 98125
    • A.O.U. Policlinico G. Martino, U.O.C. Neurologia e Malattie Neuromuscolari
  • Milan, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, UOS di Neurologia Pediatrica
  • Milano, Italy, 20162
    • Centro Clinico NeMO Fondazione Serena ONLUS Area SUD
  • Milano, Italy, 20133
    • IRCCS Istituto Neurologico Carlo Besta
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario "A.Gemelli", UOC Neuropsichiatria Infantile
  • Roma, Italy, 00146
    • Ospedale Pediatrico Bambino Gesù, Malattie Neuromuscolari e Neurodegenerative
• Netherlands
  • Leiden, Netherlands, 2300
    • Leiden University Medical Center LUMC, Albinusdreef 2
  • Nijmegen, Netherlands, 6500
    • Radboud University Medical Centre
• Serbia
  • Belgrade, Serbia, 11000
    • Clinic of Neurology and Psychiatry for Children and Youth - Neurology Department Dr. Subotic 6a,
• Spain
  • Barcelona, Spain, 08035
    • Hospital Materno-Infantil
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain
    • Hospital Universitari i Politècnic La Fe - Servicio Neurologia
  • Barcellona
    • Esplugues De Llobregat, Barcellona, Spain, 08950
      • Neuromuscular Pathology Unit - Hospital Sant Joan de Déu
• United Kingdom
  • Gobowen, United Kingdom, SY10 7AG
    • The Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust
  • London, United Kingdom, , WC1N 1EH
    • UCL Great Ormond Street Institute of Child Health, Dubowitz Neuromuscular Centre and MRC Centre for NMD
  • Newcastle Upon Tyne, United Kingdom, NE1 3BZ
    • The John Walton Muscular Dystrophy Research Centre
  • UK
    • Liverpool, UK, United Kingdom, L12 2AP
      • Alder Hey Children's Hospital NHS Trust
• United States
  • California
    • Sacramento, California, United States, 95817
      • University of California - Davis Medical Center - Devis Physical Medicine & Rehabilitation
    • San Diego, California, United States, 92123
      • Rady Children's Hospital center - UCSD Department of Neuroscience
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center, Neurology Division
  • Florida
    • Gainesville, Florida, United States, 32610
      • Child Health Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • MD Rare Disease Research, LLC
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine in St Louis Department of Neurology 660 S.Euclid Avenue, Campus Box 8111
  • Oregon
    • Portland, Oregon, United States, 97239
      • Shriners Hospitals for Children
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia Colket Translational Research Building
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Childrens Hospital of Richmond at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Must have participated in one of the previous studies with GIVINOSTAT in DMD and have attended the End of Study Visit or must have been screened in study DSC/14/2357/48 and met:

   • all the inclusion criteria and none of the exclusion criteria,
   • had a baseline vastus lateralis muscle fat fraction (VL MFF) assessed by MRS in the range ≤5% or >30%, i.e. included in"off-target" group,
   • never been randomized because, the enrollment in the off target group was completed.
2. Aged ≥6 years old;
3. Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to localregulations);

4. Subjects must be willing to use adequate contraception:

   • Contraceptive methods must since the previous GIVINOSTAT study through 3 months after the last dose of study drug, and include the following:

     • True abstinence (absence of any sexual intercourse), when in line with the preferred and usual lifestyle of the subject.
     • Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
     • Condom with spermicide and the female partner must use an acceptable method of contraception, such as an oral,
     • transdermal, injectable or implanted steroid-basedcontraceptive, or a diaphragm or a barrier method of contraception in conjunction with spermicidal jelly such asfor example cervical cap with spermicide jelly.

Exclusion Criteria:

1. Use of any pharmacologic treatment, other than corticosteroids, that might have had an effect on muscle strength or function within 3 months prior to be enrolled in this study (e.g., growth hormone); Vitamin D, calcium, and any other supplements will be allowed;
2. Use of any current investigational drug other than Givinostat;
3. 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;
4. Have a diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD;
5. Have platelets count, White Blood Cell and Hemoglobin at screening < Lower Limit of Normal (LLN)* (for abnormal screening laboratory test results (<LLN), the platelets count, White Blood Cell and Hemoglobin will be repeated once; if the repeat test result is still <LLN, then exclusionary);
6. Have Triglycerides > 300 mg/dL (3.42 mmol/L) in fasting condition at screening visit* (for abnormal screening laboratory test results (>300 mg/dL), the triglycerides will be repeated once; if the repeat test result is still >300 mg/dL, then exclusionary);
7. Have inadequate renal function, as defined by serum Cystatin C >2 x the upper limit of normal (ULN) at screening visit*. If the value is >2 x ULN, the serum Cystatin C will be repeated once; if the repeated test result is still >2 x ULN, the subject should be excluded);
8. Have heart failure (New York Heart Association Class III or IV)
9. Have a current liver disease or impairment, including but not limited to an elevated total bilirubin* (i.e. > 1.5 x ULN), unless secondary to Gilbert disease or pattern consistent with Gilbert's;
10. Have a baseline QTcF >450 msec, (as the mean of 3 consecutive readings 5 minutes apart) or history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, or family history of long QT syndrome);
11. Have a psychiatric illness/social situation rendering the potential subject unable to understand and comply with the muscle function tests and/or with the study protocol procedures.
12. Have any hypersensitivity to the components of study medication;

13. Have a sorbitol intolerance or sorbitol malabsorption or have the hereditary form of fructose intolerance.

    • the Investigators to evaluate these exclusion criteria can use the laboratory results obtained within 5 months from V1, to allow the continuity of the treatment. It is worth noting, as soon as the site will receive the laboratory results done in screening/baseline (Visit 1) visit they will check the GIVINOSTAT dose and modify it as per protocol safety rules and/or dosage modifications rules.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: givinostat; Givinostat oral suspension (10 mg/mL) twice daily in a fed state	Drug: Givinostat; suspension of givinostat (10 mg/mL)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Type, incidence, and severity of treatment related/not related adverse events(AEs) and serious adverse event (SAEs)	Through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Italfarmaco
• Collaborators: Cromsource

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2017
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: December 4, 2017
• First Submitted That Met QC Criteria: December 11, 2017
• First Posted (Actual): December 14, 2017

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 6, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: DSC/14/2357/51

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No