Clinical trial NCT02851797: Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy
Official title: Randomised, Double Blind, Placebo Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Duchenne Muscular Dystrophy
Keywords: Dystrophy
DMD
Givinostat
Lead sponsor: Italfarmaco
Sponsor class: INDUSTRY
Collaborators: name: Syneos Health
First posted: 2016-08-02
Enrollment: 179
Sex: MALE
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objective

The primary objective of the study was to establish the effects of givinostat versus placebo administered chronically over 18 months to slow disease progression in ambulant DMD subjects.

Secondary Objectives

The secondary objectives of this study were:

* To assess the safety and tolerability of givinostat versus placebo administered chronically in DMD subjects
* To evaluate the PK profile of givinostat administered chronically in DMD subjects
* To evaluate the impact on quality of life (QoL) and activities of daily living of givinostat versus placebo administered chronically.

Detailed description: This was a phase 3, randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of givinostat in ambulant subjects with DMD. This study included ambulant male paediatric subjects aged ≥ 6 years at baseline affected by DMD.

A total of 179 male ambulant subjects was randomized 2:1 (givinostat: placebo).

Subjects were 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 was planned to be 19 months.

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

Study drug should have been permanently stopped if any of the following occurred:

* severe drug-related diarrhoea;
* any drug-related Serious Adverse Event;
* QTcF \>500 msec;
* platelets count ≤50 x 10\^9/L.
* white blood cells ≤2.0 x 10\^9/L
* hemoglobin ≤8.0 g/dL

Study drug should have been temporarily stopped if any of the following occurred:

* moderate or severe diarrhoea.
* platelets count \<75 x 10\^9/L but \>50 x 10\^9/L (the treatment should been temporarily stopped and a platelets count was to be performed and re-tested until platelets normalized);
* white blood cell \<3.0 x 10\^9/L but \>2.0 x 10\^9/L (the treatment should be temporarily stopped and white blood cells had to be measured by 1 week and re-tested until white blood cells normalized);
* hemoglobin \<10.0 g/dL but \> 8.0 g/dL (the treatment should be temporarily stopped and hemoglobin had to be measured by 1 week and re-tested until hemoglobin normalized);
* Triglycerides \>300 mg/dL (3.42 mmol/L) in fasting condition (the treatment should be temporarily stopped and triglycerides measured every 2 weeks until triglycerides returned to levels below 300mg/dL (3.42 mmol/L)

In case the study drug was temporarily stopped, the study drug could be resumed at a level 20% smaller than the one at which the Adverse Event leading to temporary stop occurred, once platelets and/or white blood cell and/or hemoglobin normalized and/or triglycerides returned to levels below 300 mg/dL (3.42 mmol/L) or diarrhoea was mild.

In addition, in case a subject had a consistent (e.g., at least 2 consecutive evaluations) platelets count ≤150 x 10\^9/L and didn't meet the stopping criteria for platelets, the Investigator should have to reduce the dose by 20% of the current dose.

Only one dose reduction was allowed during the treatment period.

This trial design a single planned interim analysis. The interim was governed by an IDMC in order to solely assess futility.

Eligibility 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. Loss of ≥30 degrees of plantar flexion from the normal range of movement at the ankle joint due to contracture (i.e. fixed loss of more than 10 degrees of plantar flexion from plantigrade, assuming normal range of dorsiflexion of 20 degrees;
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 positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening15.
16. 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);
17. 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;
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.

Primary outcomes:
measure: Mean Change From Baseline in 4 Standard Stairs (4SC) Climb After 18 Months of Treatment
timeFrame: Baseline and 18 months
Secondary outcomes:
measure: Mean Change From Baseline in Time to Rise From Floor After 18 Months of Treatment
timeFrame: Baseline and 18 months
measure: Mean Change From Baseline in the Six-minute Walking Test (6MWT) After 18 Months of Treatment
timeFrame: Baseline and 18 months
measure: Mean Change From Baseline in Total North Star Ambulatory Assessment (NSAA) Score After 18 Months of Treatment
timeFrame: Baseline and 18 months
measure: Cumulative Loss of Function on the NSAA
timeFrame: over 18 months
measure: Mean Change From Baseline of Muscle Strength Normalized Overtime
timeFrame: Baseline and 18 months
measure: Mean Change From Baseline in Vastus Lateralis Muscle Fat Fraction (VL MFF) at 18 Months
timeFrame: Baseline and 18 months
measure: Number of Subjects Experiencing Treatment-emergent AEs (TEAEs), Serious AEs (SAEs), Mild TEAE Moderate TEAE, Severe TEAE
timeFrame: Baseline through end of study, that is the end of 18° month
measure: Evaluation of Acceptability/Palatability of the Oral Suspension
timeFrame: Week 4, EOS, early withdrawal
Other outcomes:
Locations:
city: Davis
country: United States
facility: Neuromuscular Research Center UC Davis Department of Physical Medicine and Rehabilitation
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital center - UCSD Department of Neuroscience
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Hartford
country: United States
facility: Connecticut Children's Medical Center - Division Neurology
state: Connecticut
city: Gainesville
country: United States
facility: Child Health Research Institute - Department of Pediatrics
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital
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: Minneapolis
country: United States
facility: University of Minnesota - Department of Neurology
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St Louis - Department of Neurology
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 Virginia Commonwealth University
state: Virginia
city: Leuven
country: Belgium
facility: University Hospitals Leuven, Neuromuscular Reference Centre, Child Neurology
city: Liege
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 - Alberta Health Services
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: Hopital Armand Trousseau I-Motion, Plateforme d'essais cliniques pédiatriques
city: Essen
country: Germany
facility: Universitatsklinikum Essen - Kinder und Jugendmedizin Neuropadiatrie
city: Hamburg
country: Germany
facility: Klinik un Policlinik fur Kinder und Jugendmedizin - Universitatsklinikum Hamburg Eppendorf
city: Munchen
country: Germany
facility: Klinikum der Uniersitat Munchen - Campus Innenstadt
city: Petach-Tikva
country: Israel
facility: Institute of Neurology - Schneider Children's Medical Center of Israel Kaplan, 14
city: Genova
country: Italy
facility: IRCCS Istituto G.Gaslini, U.O.S.D. Centro Traslazionale di Miologia e Patologie Neurodegenerative
city: Messina
country: Italy
facility: A.O.U. Policlinico G. Martino, U.O.C. Neurologia e Malattie Neuromuscolari
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, UOS di Neurologia Pediatrica
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
city: Milano
country: Italy
facility: Centro Clinico NeMO Fondazione Serena ONLUS Area SUD
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambin 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
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: Hospital Sant Joan de Déu - Neuromuscular Pathology Unit
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Materno-Infantil - Passeig de la Vall d'Hebron
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitari i Politécnic de la Fe - Servicio Neurologia
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital NHS 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 - Freeman Hospital - Newcastle University - Institute of Genetic Medicine
city: Oswestry
country: United Kingdom
facility: The Robert Jones and Agnes Hunt Orthopaedic Hospital - NHS Foundation Trust
Study officials:
affiliation: Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS
name: Eugenio Mercuri, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: