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

• Sponsor: Italfarmaco
• Collaborator: Syneos Health
• Information provided by (Responsible Party): Italfarmaco

Study Description

Brief Summary:

it is a randomised, double blind, parallel group, placebo controlled study. A total of 213 male ambulant subjects will be randomised 2:1 (givinostat:placebo).

Subjects will be 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 is planned for 19 months.

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy	Drug: givinostat; Drug: placebo	Phase 3

Detailed Description:

Givinostat or placebo oral suspension (10 mg/mL) will be administered orally as 2 oral doses daily while the subject is in fed state, according to the child's weight.

Study drug should be permanently stopped if any of the following occur:

• severe drug-related diarrhoea;
• any drug-related Serious Adverse Event;
• QTcF >500 msec;
• platelets count ≤50 x 109/L.
• white blood cells ≤2.0 x 109/L
• hemoglobin ≤8.0 g/dL

Study drug should be temporarily stopped if any of the following occur:

• platelets count <75 x 109/L but >50 x 109/L (the treatment should be temporarily stopped and a platelets count has to be performed and re-tested until platelets will be normalized);
• moderate or severe diarrhoea.
• white blood cell <3.0 x 109/L but >2.0 x 109/L (the treatment should be temporarily stopped and white blood cells have to be measured by 1 week and re-tested until white blood cells will be normalized);
• hemoglobin <10.0 g/dL but > 8.0 g/dL (the treatment should be temporarily stopped and hemoglobin has to be measured by 1 week and re-tested until hemoglobin will be normalized);
• Triglycerides >300 mg/dL (3.42 mmol/L) in fasting condition (the treatment should be temporarily stopped and triglycerides has to be measured every 2 weeks until triglycerides return to levels below 300mg/dL (3.42 mmol/L)

In case the study drug was temporarily stopped, the study drug can be resumed at a level 1/3 smaller than the one at which the Adverse Event leading to temporary stop occurred, once platelets and/or white blood cell and/or hemoglobin are normalized and/or triglycerides return to levels below 300 mg/dL (3.42 mmol/L) or diarrhoea is mild.

Two interim analyses are planned and will be conducted by the IDMC in order to ensure study integrity.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	213 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Randomised, Double Blind, Placebo Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy
Actual Study Start Date :	June 1, 2017
Estimated Primary Completion Date :	June 2020
Estimated Study Completion Date :	June 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: givinostat; Givinostat oral suspension (10 mg/mL) twice daily in a fed state	Drug: givinostat; suspension of givinostat (10 mg/mL)
Placebo Comparator: placebo; Placebo oral suspension (10 mg/mL) twice daily in a fed state	Drug: placebo; suspension manufactured to mimic givinostat

Outcome Measures

Primary Outcome Measures :

1. mean change in 4 standard stairs climb [ Time Frame: 18 months ]
   the primary endpoint is the mean change in 4 standard stairs climb test results before and after 18 months of treatment of givinostat versus placebo

Secondary Outcome Measures :

1. Other functional test as 6MWT [ Time Frame: 18 months ]
   the mean change in 6MWT
2. time to rise from floor [ Time Frame: 18 months ]
   the mean change in time to rise from floor
3. Magnetic Resonance Spetroscopy [ Time Frame: 18 months ]
   the mean change in fat fraction of vastus lateralis muscles at MRS
4. North Star Ambulatory Assessment [ Time Frame: 18 months ]
   the mean change in North Star Ambulatory Assessment
5. Muscle strength evaluated by knee extension, elbow flexion [ Time Frame: 18 months ]
   the mean change of muscle strength evaluated by knee extension, elbow flexion as measured by hand-held myometry (HHM)

Eligibility Criteria

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Ages Eligible for Study:	6 Years to 17 Years (Child)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. 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;
2. Have DMD diagnosis confirmed by genetic testing;
3. Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to local regulations);
4. 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;
5. Have the mean of 2 screening 4SC assessments ≤8 seconds;
6. Have time to rise from floor between ≥3 and <10 seconds at screening
7. Have manual muscle testing (MMT) of quadriceps at screening Grade - 3;
8. 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.
9. Subjects must be willing to use adequate contraception.

Exclusion Criteria:

1. Have exposure to another investigational drug within 3 months prior to the start of study treatment;
2. Have exposure to idebenone within 3 months prior to the start of study treatment;
3. Have exposure to any dystrophin restoration product (e.g., Ataluren, Exon skipping) within 6 months prior to the start of study treatment;
4. 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;
5. 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;
6. Ankle joint contractures due to a fixed loss of ≥10 degrees of dorsiflexion from plantagrade assuming a normal range of dorsiflexion of 20 degree;
7. 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;
8. 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;
9. Have a diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD;
10. Have platelets count at screening < Lower Limit of Normal (LLN);
11. Have symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction <50% at screening;
12. Have a current or history of liver disease or impairment;
13. Have inadequate renal function, as defined by serum Cystatin C >2 x the upper limit of normal (ULN);
14. Have Triglycerides > 300 mg/dL (3.42 mmol/L) in fasting condition at screening visit;
15. 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);
16. 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;
17. Have any known allergic reaction to givinostat or any of its excipients.
18. Have any hypersensitivity to the components of study medication;
19. Have a sorbitol intolerance or sorbitol malabsorption, or have the hereditary form of fructose intolerance.
20. 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.

Contacts and Locations

Contacts

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Contact: Reference Study ID Number EPYDIS (DSC/14/2357/48)	+39 026443 ext 2524	patientadvocacy@italfarmaco.com

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Locations

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United States, California
Neuromuscular Research Center UC Davis Department of Physical Medicine and Rehabilitation	Recruiting
Davis, California, United States, 95817
Contact: Erica Goude emgoude@ucdavis.edu
Principal Investigator: Craig McDonald, MD
David Geffen School of Medicine - UCLA Neurology	Recruiting
Los Angeles, California, United States, 90095
Contact: Dianne de Guzman DDeGuzman@mednet.ucla.edu
Principal Investigator: Perry Shieh, MD
Rady Children's Hospital center - UCSD Department of Neuroscience	Recruiting
San Diego, California, United States, 92123
Contact: Jessica Reit jreit@ucsd.edu
Principal Investigator: Chamindra Konersman, MD
United States, Colorado
Children's Hospital Colorado	Recruiting
Aurora, Colorado, United States, 80045
Contact: Kyle Kusmik, MD Kyle.Kusmik@childrenscolorado.org
Principal Investigator: Michele Yang, MD
United States, Connecticut
Connecticut Children's Medical Center - Division Neurology	Recruiting
Hartford, Connecticut, United States, 06106
Contact: Vikki Palmer VPalmer@connecticutchildrens.org
Principal Investigator: Gyula Acsadi, MD
United States, Florida
Child Health Research Institute - Department of Pediatrics	Recruiting
Gainesville, Florida, United States, 32610
Contact: Christina Marie Cousins, MD couscm@peds.ufl.edu
Principal Investigator: Barry Byrne, MD
Nemours Children's Hospital	Recruiting
Orlando, Florida, United States, 32827
Contact: Virginia Rizzo, MD Virginia.Rizzo@nemours.org
Principal Investigator: Richard Finkel, MD
United States, Iowa
University of Iowa Children's Hospital	Recruiting
Iowa City, Iowa, United States, 52242
Contact: Corey McDaniel corey-mcdaniel@uiowa.edu
Principal Investigator: Katherine Mathews, MD
United States, Michigan
Wayne State University - University Pediatrics - Children's Hospital of Michigan	Withdrawn
Detroit, Michigan, United States, 48201
United States, Minnesota
University of Minnesota - Department of Neurology	Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Natalya Burlakova burla019@umn.edu
Principal Investigator: Georgios Manousakis, MD
United States, Missouri
Washington University School of Medicine in St Louis - Department of Neurology	Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Alyssa Sonsoucie amsonsoucie@wustl.edu
Principal Investigator: Craig Craig Zeidman, MD
United States, Oregon
Shriners Hospitals for Children	Recruiting
Portland, Oregon, United States, 97239
Contact: Paige Lemhouse plemhouse@shrinenet.org
Principal Investigator: Erika Finanger, MD
United States, Pennsylvania
The Children's Hospital of Philadelphia	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Khrystine Ford FORDKA@email.chop.edu
Principal Investigator: Gihan Tennekoon, MD
United States, Virginia
Virginia Commonwealth University Childrens Hospital of Richmond at Virginia Commonwealth University	Recruiting
Richmond, Virginia, United States, 23298
Contact: Kathryn O'Hara, MD kathryn.ohara@vcuhealth.org
Principal Investigator: Amy Harper, MD
Belgium
University Hospitals Leuven, Neuromuscular Reference Centre, Child Neurology	Recruiting
Leuven, Belgium, 03000
Contact: Nathalie Goemans, MD nathalie.goemans@uzleuven.be
Principal Investigator: Nathalie Goemans, MD
Hospital de La Citadelle, Centre de Référence des Maladies Neuromuscolaires (CRMN)	Recruiting
Liege, Belgium, 04000
Contact: Laurent Servais, MD l.servais@institut-myologie.org
Principal Investigator: Laurent Servais, MD
Canada, Alberta
insmen Research Centre - Alberta Children's Hospital - Alberta Health Services	Recruiting
Calgary, Alberta, Canada, T3B6A8
Contact: Jean Mah, MD Jean.Mah@albertahealthservices.ca
Principal Investigator: Jean Mah, MD
Canada, British Columbia
The University of British Columbia, Children's and Womens Health Centre of BC Branch	Recruiting
Vancouver, British Columbia, Canada, V6H 3V4
Contact: Kathryn Selby, MD kselby@cw.bc.ca
Principal Investigator: Kathryn Selby, MD
Canada, Ontario
Holland Bloorview Kids Rehabilitation Hospital	Recruiting
Toronto, Ontario, Canada, M4G1R8
Contact: Gloria Lee glee@hollandbloorview.ca
Principal Investigator: Laura McAdam, MD
France
CHU de Nantes - Hotel-Dieu - Hopital Nord Laennec, rez-de-chausse haut ail Ouest	Recruiting
Nantes, France, 44093
Contact: Yann Pereon, MD Yann.Pereon@univ-nantes.fr
Principal Investigator: Yann Pereon, MD
Hopital Armand Trousseau I-Motion, Plateforme d'essais cliniques pédiatriques	Recruiting
Paris, France, 75012
Contact: Teresa Gidaro, MD t.gidaro@institut-myologie.org
Principal Investigator: Teresa Gidaro, MD
Germany
Universitatsklinikum Essen - Kinder und Jugendmedizin Neuropadiatrie	Recruiting
Essen, Germany, 45122
Contact: Ulrike Schara, MD ulrike.schara@uk-essen.de
Principal Investigator: Ulrike Schara, MD
Klinik un Policlinik fur Kinder und Jugendmedizin - Universitatsklinikum Hamburg Eppendorf	Recruiting
Hamburg, Germany, 20246
Contact: Jessika Johannssen, MD j.johannsen@uke.de
Principal Investigator: Jessika Johannssen, MD
Klinikum der Uniersitat Munchen - Campus Innenstadt	Recruiting
Munchen, Germany, 80337
Contact: Astrid Blaschek, MD Astrid.Blaschek@med.uni-muenchen.de
Principal Investigator: Wolfgang Muller-Felber, MD
Italy
IRCCS Istituto G.Gaslini, U.O.S.D. Centro Traslazionale di Miologia e Patologie Neurodegenerative	Recruiting
Genova, Italy, 16147
Contact: Claudio Bruno, MD claudiobruno@ospedale-gaslini.ge.it
Principal Investigator: Claudio Bruno, MD
A.O.U. Policlinico G. Martino, U.O.C. Neurologia e Malattie Neuromuscolari	Recruiting
Messina, Italy, 98125
Contact: Giuseppe Vita, MD vitag@unime.it
Principal Investigator: Giuseppe Vita, MD
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, UOS di Neurologia Pediatrica	Recruiting
Milano, Italy, 20122
Contact: Giacomo Comi, MD giacomo.comi@unimi.it
Principal Investigator: Giacomo Comi, MD
Fondazione IRCCS Istituto Neurologico Carlo Besta	Recruiting
Milano, Italy, 20133
Contact: Riccardo Masson, MD Riccardo.Masson@istituto-besta.it
Principal Investigator: Riccardo Masson, MD
Ospedale Pediatrico Bambin Gesù, Malattie Neuromuscolari e Neurodegenerative	Recruiting
Roma, Italy, 00146
Contact: Enrico Bertini, MD enricosilvio.bertini@opbg.net
Principal Investigator: Enrico Bertini, MD
Fondazione Policlinico Universitario "A.Gemelli", UOC Neuropsichiatria Infantile	Recruiting
Roma, Italy, 00168
Contact: Eugenio Mercuri, MD eugeniomaria.mercuri@policlinicogemelli.it
Principal Investigator: Eugenio Mercuri, MD
Netherlands
Leiden University Medical Center LUMC	Recruiting
Leiden, Netherlands, ZH 2300 RC
Contact: Martha Mosselman, MD M.H.Mosselman@lumc.nl
Principal Investigator: Erik Niks, MD
Radboud University Medical Centre	Recruiting
Nijmegen, Netherlands, 6500
Contact: Imelda de Groot, MD Imelda.deGroot@radboudumc.nl
Principal Investigator: Imelda de Groot, MD
Spain
Hospital Sant Joan de Déu - Neuromuscular Pathology Unit	Recruiting
Esplugues de Llobregat, Barcelona, Spain, 08950
Contact: Andres Nascimento, MD anascimento@sjdhospitalbarcelona.org
Principal Investigator: Andres Nascimento, MD
Hospital Materno-Infantil - Passeig de la Vall d'Hebron	Recruiting
Barcelona, Spain, 08035
Contact: Francina Munell, MD francina.munell@vhir.org
Principal Investigator: Francina Munell, MD
Hospital Universitari i Politécnic de la Fe - Servicio Neurologia	Recruiting
Valencia, Spain, 46026
Contact: Juan Jesus Vilchez, MD vilchez_jje@gva.es
Principal Investigator: Juan Jesus Vilchez, MD
United Kingdom
Alder Hey Children's Hospital NHS Trust	Recruiting
Liverpool, United Kingdom, L12 2AP
Contact NMR@alderhey.nhs.uk
Principal Investigator: Stefan Spinty, MD
UCL Great Ormond Street Institute of Child Health, Dubowitz Neuromuscular Centre and MRC Centre for NMD	Recruiting
London, United Kingdom, EC1N 1EH
Contact: Mariacristina Scoto, MD m.scoto@ucl.ac.uk
Principal Investigator: Mariacristina Scoto, MD
The John Walton Muscular Dystrophy Research Centre - Freeman Hospital - Newcastle University - Institute of Genetic Medicine	Recruiting
Newcastle upon Tyne, United Kingdom, NE1 3BZ
Contact: May Tiet may.tiet@newcastle.ac.uk
Principal Investigator: Michaela Guglieri, MD
The Robert Jones and Agnes Hunt Orthopaedic Hospital - NHS Foundation Trust	Recruiting
Oswestry, United Kingdom, SY 10 7AG
Contact: Sarah Turner, MD Sarah.Turner2@rjah.nhs.uk
Principal Investigator: Tracey Willis, MD

Sponsors and Collaborators

Italfarmaco

Syneos Health

More Information

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Responsible Party:	Italfarmaco
ClinicalTrials.gov Identifier:	NCT02851797 History of Changes
Other Study ID Numbers:	EPYDIS (DSC/14/2357/48)
First Posted:	August 2, 2016
Last Update Posted:	May 1, 2019
Last Verified:	April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

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Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases	Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked