Clinical trial NCT03373968: Givinostat in Duchenne's Muscular Dystrophy Long-term Safety and Tolerability Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Duchenne Muscular Dystrophy
Lead sponsor: Italfarmaco
Sponsor class: INDUSTRY
Collaborators: name: Cromsource
First posted: 2017-12-14
Enrollment: 206
Sex: MALE
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: Through study completion, an average of 1 year
Secondary outcomes:
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California - Davis Medical Center - Devis Physical Medicine & Rehabilitation
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital center - UCSD Department of Neuroscience
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center, Neurology Division
state: Connecticut
city: Gainesville
country: United States
facility: Child Health Research Institute
state: Florida
city: Atlanta
country: United States
facility: MD Rare Disease Research, LLC
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Children's Hospital
state: Iowa
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St Louis Department of Neurology 660 S.Euclid Avenue, Campus Box 8111
state: Missouri
city: Portland
country: United States
facility: Shriners Hospitals for Children
state: Oregon
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia Colket Translational Research Building
state: Pennsylvania
city: Richmond
country: United States
facility: Virginia Commonwealth University Childrens Hospital of Richmond at
state: Virginia
city: Leuven
country: Belgium
facility: University Hospitals Leuven, Neuromuscular Reference Centre, Child Neurology
city: Liège
country: Belgium
facility: Hospital de La Citadelle, Centre de Référence des Maladies Neuromuscolaires (CRMN)
city: Calgary
country: Canada
facility: Kinsmen Research Centre - Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: The University of British Columbia, Children's and Womens Health Centre of BC Branch
state: British Columbia
city: Toronto
country: Canada
facility: Holland Bloorview Kids Rehabilitation Hospital
state: Ontario
city: Nantes
country: France
facility: CHU de Nantes - Hotel-Dieu - Hopital Nord Laennec, rez-de-chausse haut ail Ouest
city: Paris
country: France
facility: Hôpital Armand Trousseau I-Motion - Plateforme d'essais cliniques pédiatriques Bâtiment Lemariey - Porte 20 * 2ème étage 26 Avenue du Dr Arnold Nette
city: Essen
country: Germany
facility: Universitätsklinikum Essen - Kinder-und Jugendmedizin Neuropadiatrie
city: Hamburg
country: Germany
facility: Klinik- und Poliklinik fur Kinder- und Jugendmedizin, Universitatsklinikum HamburgEppendorf, Martinistr. 52
city: München
country: Germany
facility: Klinikum der Universitat Munchen, Campus Innenstadt, Lindwurmstr. 4
city: Petach-Tikva
country: Israel
facility: Institute of Neurology - Schneider Children's Medical Center of Israel Kaplan, 14
city: Genova
country: Italy
facility: U.O.S.D. Centro Traslazionale di Miologia e Patologie Neurodegenerative, Building 16 - ground floor IRCCS Istituto Giannina Gaslini,
city: Messina
country: Italy
facility: A.O.U. Policlinico G. Martino, U.O.C. Neurologia e Malattie Neuromuscolari
city: Milano
country: Italy
facility: IRCCS Istituto Neurologico Carlo Besta
city: Milano
country: Italy
facility: Centro Clinico NeMO Fondazione Serena ONLUS Area SUD
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, UOS di Neurologia Pediatrica
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù, Malattie Neuromuscolari e Neurodegenerative
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario "A.Gemelli", UOC Neuropsichiatria Infantile
city: Leiden
country: Netherlands
facility: Leiden University Medical Center LUMC, Albinusdreef 2
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
city: Belgrade
country: Serbia
facility: Clinic of Neurology and Psychiatry for Children and Youth - Neurology Department Dr. Subotic 6a,
city: Esplugues De Llobregat
country: Spain
facility: Neuromuscular Pathology Unit - Hospital Sant Joan de Déu
state: Barcellona
city: Barcelona
country: Spain
facility: Hospital Materno-Infantil
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe - Servicio Neurologia
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital NHS Trust
state: UK
city: Gobowen
country: United Kingdom
facility: The Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: UCL Great Ormond Street Institute of Child Health, Dubowitz Neuromuscular Centre and MRC Centre for NMD
city: Newcastle Upon Tyne
country: United Kingdom
facility: The John Walton Muscular Dystrophy Research Centre
Study officials:
References: