Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy
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|ClinicalTrials.gov Identifier: NCT02851797|
Recruitment Status : Completed
First Posted : August 2, 2016
Results First Posted : February 2, 2023
Last Update Posted : February 2, 2023
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.
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.
|Condition or disease||Intervention/treatment||Phase|
|Duchenne Muscular Dystrophy||Drug: givinostat Drug: placebo||Phase 3|
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:
- Deflazacort daily regimen
- Deflazacort intermittent regimen
- Other steroids daily regimen
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||179 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|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 6, 2017|
|Actual Primary Completion Date :||February 22, 2022|
|Actual Study Completion Date :||February 22, 2022|
Active Comparator: givinostat
Givinostat oral suspension (10 mg/mL) twice daily
The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below:
Givinostat or placebo starting dose
Other Name: ITF2357
Placebo Comparator: placebo
Placebo oral suspension (10 mg/mL) twice daily
The oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
- Mean Change From Baseline in 4 Standard Stairs (4SC) Climb After 18 Months of Treatment [ Time Frame: Baseline and 18 months ]The time (in seconds) to climb 4 standard-sized stairs is a TFT that represents stair-climbing ability. The test was evaluated by qualified functional evaluators (ie, physiotherapists) who were different from the site personnel who reviewed subjects' safety results. The test was performed in a standardised manner described in a specific site manual. Baseline 4SC was the measurement taken at the randomization assessment, unless this was missing, in which case baseline was taken as the last non missing value recorded prior to or on the date of first study treatment. The shorter the time, the better the outcome.
- Mean Change From Baseline in Time to Rise From Floor After 18 Months of Treatment [ Time Frame: Baseline and 18 months ]An analysis of time (in seconds) to rise from the floor by change from baseline at 18 months is presented for the Target Population in the ITT analysis set. The shorter the time, the better the outcome.
- Mean Change From Baseline in the Six-minute Walking Test (6MWT) After 18 Months of Treatment [ Time Frame: Baseline and 18 months ]
This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes.
The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment. A modified version of the 6MWT recommended by American Thoracic Society (2002) for use in adults was performed.
The longer the walked distance the better the outcome.
- Mean Change From Baseline in Total North Star Ambulatory Assessment (NSAA) Score After 18 Months of Treatment [ Time Frame: Baseline and 18 months ]The total North Star Ambulatory Assessment (NSAA) is a 17-item rating scale that is used to measure functional motor abilities in ambulant children with Duchenne Muscular Dystrophy (DMD). It is usually used to monitor the progression of the disease and treatment effects. The 17 items of the NSAA, ranging from standing to running 10 meters, were graded using the standard score card with each assessment rated as 0 - unable to achieve independently, 1 - modified method but achieves goal independent of physical assistance from another, or 2 - normal with no obvious modification of activity. This scale is ordinal with 0 as the minimum score (indicating full disfunctionality, i.e. the worst outcome) and with 34 as the maximum score indicating fully-independent function (the best outcome).
- Cumulative Loss of Function on the NSAA [ Time Frame: over 18 months ]
Subject cumulative number of failures across all postbaseline visits was the endpoint of interest for analysis.
For each subject at each postbaseline visit, failure to perform each of the 17 items of the NSAA was assessed, where "failure" was defined as a score transition from 2 or 1 at baseline to 0 at the respective visit. The total number of failed items for the visit was calculated (maximum of 17 failed items per visit per subject). The subject's cumulative number of failures across all visits was the sum of the total failures at each postbaseline visit.
- Mean Change From Baseline of Muscle Strength Normalized Overtime [ Time Frame: Baseline and 18 months ]The mean change of muscle strength normalized was evaluated by knee extension and elbow flexion normalized by subject weight, both measured by hand-held myometry (HHM).
- Mean Change From Baseline in Vastus Lateralis Muscle Fat Fraction (VL MFF) at 18 Months [ Time Frame: Baseline and 18 months ]Vastus lateralis muscle fat fraction (VL MFF) was expressed as fat infiltration in this muscle. Fat infiltration was assessed by Magnetic Resonance (MRS).
- Number of Subjects Experiencing Treatment-emergent AEs (TEAEs), Serious AEs (SAEs), Mild TEAE Moderate TEAE, Severe TEAE [ Time Frame: Baseline through end of study, that is the end of 18° month ]
Adverse Events are unfavorable changes in health, including abnormal laboratory findings, that occur in trial participants during the clinical trial or within a specified period following the trial.
Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered Serious Adverse Events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned.
- Evaluation of Acceptability/Palatability of the Oral Suspension [ Time Frame: Week 4, EOS, early withdrawal ]Acceptability and palatability of the oral suspension over time are presented. More in details, child perception of the medicine at the three timepoints hereunder specified; parent perception of the medicine based on the child's reaction at the same three timepoints; and parent problems administering the medication at the same timepoints are reported.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02851797
|Principal Investigator:||Eugenio Mercuri, MD, PhD||Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS|